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THE ELECTROCHEMICAL SYNTHESIS OF 3-tert-BUTYL-4-METHOXYBENZALDEHYDE

By SIVUYILE EMMANUEL QUSHEKA

Baccalareus Technologiae Chemistry, Nelson Mandela Metropolitan University

A dissertation submitted in fulfilment of the requirements for the Masters Degree in Technology: Chemistry

In the Faculty of Science at the NELSON MANDELA METROPOLITAN UNIVERSITY

January 2007

Promoter Co-promoter

: Dr S. Gouws : Prof B. Zeelie

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ACKNOWLEDGEMENTS
My promoters Dr S. Gouws, Prof. B. Zeelie for their help, support, advice and guidance The National Research Foundation, Center of Excellence and DAAD for their financial support My mother and the rest of my family for all their support and guidance, I thank God for them. The staff and my fellow students at the Chemistry department are also thanked for their assistance and friendship

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SUMMARY
This project was concerned with the evaluation of three potential synthetic routes for 3-tert-butyl-4-methoxybenzaldehyde, a useful fine chemical intermediate and ingredient in many sunscreen agents. The three synthetic routes all involved the selective oxidation of the 3-tert-butyl-4-methoxytoluene to the desired benzaldehyde by (a) catalytic air oxidation, (b) direct electrochemical oxidation, and (c) indirect electrochemical oxidation. In order to decide whether catalytic oxidation should precede the alkylation of 4-methoxytoluene, the selective oxidation using the well-known cobalt(II)bromide catalyst system in acetic acid solutions were investigated with the view to determine whether increased electron density on the aromatic ring improves selectivity to the desired benzaldehyde or not. In addition, the effect of various important reaction variables was also investigated. These studies showed that increased electron density, hence increased substitution, increases the desired benzaldehyde selectivity. In addition, while reaction conditions such as reaction temperature, catalyst concentration, water concentration, etc. may be optimised for maximum 3-tert-butyl-4methoxybenzaldehyde yields (~80%), such yields can only be achieved at relatively low (<40%) alkoxytoluene conversions. The direct electrochemical oxidation of 3-tert-butyl-4-methoxytoluene was investigated in methanol solutions containing various supporting electrolytes and using constant current electrolysis with the intention of optimizing the production of 3-tert-butyl-4-methoxybenzyl dimethyl acetal which can later be hydrolyzed using sulfuric acid to the 3-tert-butyl-4-methoxybenzaldehyde. In this study, various parameters such as supporting electrolyte and electrodes were studied. Previous studies showed undoubtedly that methanol as a solvent gave better results amongst the rest of the solvents.

4 Indirect route was also studied as a method of synthesizing 3-tert-butyl-4methoxybenzaldehyde and compared to the direct electro synthesis KEY WORDS: p-Methoxyanisole. . Catalytic air oxidation. 3-tert-butyl-4-methoxytoluene. Electrochemical oxidation. 3-tert-butyl-4methoxybenzaldehyde.

.......................................15 1..1 Introduction ........2.......................................1 Hydroxybenzaldehydes ........26 1.......................16 1..37 2...........................4 Overview of Synthetic Routes to Hydroxybenzaldehyde ..................1..1............4..............................4..4.............2......2.............................. .......................8 1.........................3......38 2..................................................17 1..............................................................1...3...............17 1...........2 4-Hydroxybenzaldehyde...............................................................................2.....................................................4...............................3 Routes from Cresols.............................................4...................2.................41 2......................................3...........43 2..................1 General ...........................................29 1.............................................................16 1...............8 INTRODUCTION.............38 2................2 Vilsmeier Aldehyde Synthesis ......2........26 1................4.......3 Saligenin Reaction...3 Overview of hydroxy.....................1 2-Hydroxybenzaldehyde.............................................2...33 CHAPTER 2 .........................4........31 1................13 1..............................2 Synthesis of 3-tert-butyl-4-methoxytoluene................1 Cyclic voltammogram studies....................1 Side-Chain Halogenation...................................2....................................2..............................................................30 1....................................2 Overview of the Flavour and Fragrance Industry.......1 The Reimer-Tiemann reaction ....................................4 3-Tert-butyl-4-methoxytoluene oxidation using Ce(IV) methanesulfonate 45 .............4.......1...............................2............................2 Uses.............................4..................1 General ...................24 1.......35 EXPERIMENTAL ........................2 SYNTHETIC PROCEDURES.......4.......38 2.....8 1...................28 1....................5 TABLE OF CONTENTS SUMMARY......3..........1 Materials........................................................................................2.........11 1........................................3......2...................................3 Synthesis of Ce(IV) methanesulfonate solution..................................3.............................2 International Flavour and Fragrance Industry .......35 2.........2....3.................................................4........................................2.......................................................................................................................35 2.................4................28 1.......4.........................2.3.........................3..........1 Catalytic air oxidation studies ...............................18 1...4 Glyoxilic Acid Condensation.........................................................................................2.........25 1........................................................................1 Reagents for synthesis.................35 2..............................................................................................................3 Electochemical Oxidation .2..............17 1................25 1.....................................2 4-Hydroxyacetophenone.................1 Introduction ......................................................37 2..............1 Reagents for HPLC analysis...2 Reagents for Analysis ..........45 2.........................2 Synthesis of Ce(III) Carbonate.....45 2...3 Direct electrochemical synthesis of 3-tert-butyl-4-methoxy-benzaldehyde..................................3 Chapter 1..................2 Catalytic Air Oxidation ....................................1...2..11 1...............................2.....................................................................2.......4 Indirect electrochemical synthesis of 3-t-butyl-4-methoxy-benzaldehyde using Ce(IV)...and alkoxybenzaldehydes ..........43 2.......30 1..........................................................3 South African Flavour and Fragrance Industry .......................................................4.......2 Routes from Phenol..........................................................................

.................................................................53 3.........................3 Mechanistic considerations .9 NMR Spectroscopy ..............................1....................................64 3........................................1 Catalytic Air Oxidation ...................51 2......48 2...............52 CHAPTER 3 ..............50 2......................................................................................71 3...5 Catalytic air oxidation: Effect of water concentration ...6 Recycling of Ce (IV) in methanesufonic acid..................................3..........2...2.............6 Catalytic Air Oxidations: Concluding Remarks ....................................3............54 3...........3.................3.............47 2.........................5 Indirect Electrochemical Oxidations: Concluding Remarks ................................................7 pH Determinations .......77 3.49 2..3..................1 General .......1................................78 3...8 Direct electrolysis in an undivided electrochemical cell.4 Supporting Electrolyte Investigations ...2 Catalytic air oxidation: Nature of the substrate ..2......3............................5 Product distribution diagrams.....7 Oxidations using cerium(IV) ammonium nitrate ..........................62 3.................2......................................2.................50 2.........51 2............3...........................................53 CHAPTER 3 .......3......................................................................6 UV/Visible Spectrophotometry ...5...............................2...48 2.47 2.......................3 Electrochemical alkoxylation ..........................51 2.............88 3........................53 3.........................2 Stability Studies .3 Conductivity Studies ...................3 Sodium perchlorate ...........2.............1.............................69 3..................................77 3......3........................1.......3..............3 Catalytic air oxidation: Reaction temperature ..........................85 3..............................................76 3.3 Ceric Ammonium Nitrate.......................3.............................................................65 3........................................................81 3.............1.....51 2..........................................................................3..................................10 Fourier Transform Infrared Spectroscopy ....................1 Introduction .................................................2 Indirect oxidation of 3-tert-butyl-4-methoxytoluene.....................................................4.........................70 3....2..............1 Recycling of cerium ammonium nitrate ....3..........2........2.............................................................................3 Direct Electrochemical Oxidations ..........................................1 Conductivity Studies of the Supporting Electrolytes ..88 3........3................................................................5 Preparation of cerium(IV) methanesulfonate from commercial Ce2(CO3)3 46 2......................................................................................................1 Constant current and constant potential electrolysis.............. sodium salt ............53 3.......5 Differential Scanning Calorimetry....3.......4 Catalytic air oxidation: Effect of catalyst concentration....3...................................1.............................................65 3..................................3....................4........8 Coulometric Analysis ....4 Cyclic voltammetry.....51 2.............................65 3........................................86 3................5....6 2.........87 3..............................7.............3 ANALYTICAL TECHNIQUES ...........................46 2.................2 Undivided vs Divided ....................61 3...........................3.............................4 Indirect electrochemical oxidation of 3-tert-butyl-4-methoxytoluene using Cerium(IV) Methanesulfonate.........................1 Gas Chromatography – Mass Spectrometry .................................................1 Benzenesulfonic acid.....3....................79 3.......53 RESULTS AND DISCUSSION .92 3..............................5.2 Limitations in Solubility during Organic Electrochemical Processing..........3....................3............95 ...........2 Sulfuric acid ..................................2 High Pressure Liquid Chromatography..................................46 2.

........1..5 Catalytic Air Oxidations: Concluding Remarks ..................................4 Potassium fluoride.....2............... 106 4.....................................................................................5..1.........1............2 Catalytic air oxidation: Reaction temperature ....... 104 4.......................................... 105 4........... 102 Chapter 4..................1..............4 Catalytic air oxidation: Effect of water concentration .................1....................................................................................................................3 Direct Electrochemistry ............2.............................. 107 4......2 Methanesulfonic reactions and the effect of a co-solvent .............................................................3 Catalytic air oxidation: Effect of catalyst concentration....................................7 3....................................................2 Indirect Electrochemical Oxidations................................................... 107 4...............................1 Nature of the substrate ............................................................................................1 Catalytic Air Oxidation ............................................. 108 REFERENCES:................................ 104 SUMMARY AND CONCLUDING REMARKS....99 3.... 104 4..... 110 . 106 4................. 105 4............ 107 4.3.....6 Direct Electrolysis: Summary and concluding remarks.................. 108 4..........1 Ceric Ammonium Reactions ..............................3............

8 Chapter 1 INTRODUCTION 1. it has missed the opportunity to take a share of the high growth markets of the nineties. In early 2002. The document identified a number of requirements for micro-economic reform in South Africa. Indeed. distance from low-cost raw materials and inadequate human resources. food and flavour additives and adhesives. the chemical industry. in view of its potential for growth and development. as indeed is acknowledged in the . commodity-based industry that has not managed to break through its endemic growth barriers of a small local market. the Department of Trade and Industry published a document entitled Accelerating Growth and Development: The Contribution of an Integrated Manufacturing Strategy2. the South African chemical industry1 has remained static over the last ten years. the purpose of which was to ‘invigorate the production of goods and services and create the conditions necessary for the retention and growth of output and employment in other sectors of the economy’. high cost of capital. Furthermore. was highlighted as worthy of increased attention and a number of specific objectives were defined. Notwithstanding a number of strategic processes whose objectives were to increase downstream value-addition and integration.1 General Apart from several notable exceptions. However. speciality surfactants. the Integrated Manufacturing Strategy (IMS)3 will on its own not be able to achieve the desired outcomes of growth and development. it has lost critical manufacturing capacity and skills. it has failed to expand and diversify significantly into higher value-added products. including the promotion of competitiveness and the development of customised services. active pharmaceutical ingredients. including such areas as electronic chemicals. in many cases. it remains predominantly an upstream.

particularly chemical starting materials. • Support for existing development efforts in low-cost diagnostics. intermediates and products”. the Chemical Sector Task Team (CSTT) proposed several strategic interventions4. and that this lag will reduce the country’s competitiveness in world markets. bio-diesel and products from alpha-olefins. including: • Establishment of a new technology platform that will develop technologies to decrease economies of scale for chemical plants and hence enable smaller production facilities to compete against the mega plants. In order to redress this situation. In this context. which is concerned that South Africa’s R&D capability is lagging significantly behind competitor developing countries.9 document. specifically addresses the two strategic interventions highlighted above and this particular project forms part of this overall Small Volume Chemicals Program which focuses on “the development of chemical and technological expertise for the synthesis and/or production of phenolic chemicals. highly innovative and lateral solutions to leverage South Africa’s manufacturing industry. aroma chemicals production. This particular project deals with the conversion of simple phenolic compounds to higher-value derivatives by catalytic oxidation . to underpin the new IMS and to stimulate investment in key technology. called “c*change” identified several major research programs with a view to support other initiatives such as the IMS referred to above. This Centre of Excellence. The latter aspect has been a specific focus of the NACI. the outcomes will also require appropriate and effective human resource development and technology strategies. Towards the end of 2004 the Department of Science and Technology launched its “Research Centres of Excellence Program” including a Centre of Excellence in Catalytic Processing housed at the University of Cape Town. For instance. NACI commissioned an Advanced Manufacturing and Logistics Strategy with the requirement that the recommendations provide some radical. One of these programs. and development of biodegradable and high performance polymers. the Small Volume Chemicals Programme.

the synthesis may involve either an alkylation or oxidation step as the initial reaction step. More precisely.1 illustrates the two major options when using 4-methylanisole as starting material for this synthesis. this project aims to evaluate various approaches to the synthesis of alkyl-substituted alkoxybenzaldehydes with the view to identify the most promising route for the production of the said aldehydes. e. The latter group of compounds.10 technologies. As is illustrated above. phenols to hydroquinones/benzoquinones and alkylphenols to phenolic ketones or aldehydes and derivatives thereof. Scheme 1. particularly in view of the fact that . the world’s largest producer of phenolic compounds. which are of particular interest to the aroma (fragrance and flavour) industry. may be produced from locally (RSA) available feedstock from the company Merisol.1 Routes to alkyl-alkoxybenzaldehydes from 4-methylanisole.g. Scheme 1. This choice is extremely important to optimize the selectivity of the final reaction product.

and essential oils are naturally occurring. and indirect electrochemical oxidations using a mediator substance. largely insensitive to commodity cycles and relatively recession-resistant come from the industry’s close unity with the health.1 Introduction Aroma chemicals are used as the foundation of flavour and fragrance for giving attractive taste and aroma to processed foods and beverages and contributing pleasing scents to perfumes. volatile products obtained from various parts of plants). direct electrochemical oxidations. for example in the above case the presence of the additional alkyl group may either promote selectivity. The formulation may . chemically defined substances which act on the sense of smell and taste. personal care and food beverage markets.2 Overview of the Flavour and Fragrance Industry 1. or decrease selectivity. In view of the critical nature of the oxidation step to ensure high yields of final product. The world-wide flavour and fragrance industry generally earns returns in excess of the chemical industry average. The industry is comprised of the following broad segments: • Isolation of synthetic and natural aroma chemicals or essential oils/ natural products (Aroma chemicals are single. Such further oxidation reactions will depend on the structure of the substrate being oxidized. The relatively stable revenues. • Compounding of these products into flavour and fragrance formulations tailored to meet specific customer requirements.11 partial oxidation reactions are particularly prone to undergo further oxidation reactions which lower the selectivity. 1. These are: Catalytic air oxidation. three oxidation technologies will be evaluated.2. toiletries and detergents.

food and beverage market etc. Figure 1.12 contain aroma chemicals as well as other essential oils and natural extracts.1) depicts the full flavour and fragrance value chain. • The sale and use of these formulations in the production of personal care and pharmaceutical active ingredients.1: Flavour and Fragrance value chain . The following schematic diagram (Figure 1.

diluents and carriers. beverages. camphor. into terpene aroma chemicals such as citral and linalool. foods. the formulation may contain other additives such as essential oils and natural extracts. 1.g.800 aroma chemicals are approved for use in flavour and fragrance formulations world-wide. only a few hundred are produced in volumes over 50 tons for the merchant market. III. among other things. Other than the solvents. toiletries. True Isolates: Single aroma chemicals which are extracted from natural materials and subjected only to further processes of purification (e. There are various routes that can be used for the production of aroma chemicals: I. This includes the conversion of crude sulfonated turpentine. or a pleasing scent to consumer products such as perfumes. . II. Figure 1. Chemically modified derivatives: Made by converting isolate products into a specific chemical product by subjecting them to various chemical processes. detergents and pharmaceutical products.2 illustrates a breakdown of the use of flavour compositions in consumer end products5.2. 2. Compounded flavour and fragrance products are thus complex blends designed to impart either attractive taste or aroma to processed foods and beverages. True synthetic chemicals: It includes chemicals produced by synthesis from natural aromatic compounds and from synthetic feed stock such as petrochemicals. household cleaners etc. a by-product of the kraft paper pulping process. citral and menthol).13 Approximately.2 International Flavour and Fragrance Industry Flavour and fragrance formulations are widely used globally to enhance. However.

which shows that the USA accounts for 31% of the market. This is confirmed by the global consumption usage of flavour and fragrances.3 illustrates a breakdown of the use of fragrance compositions in consumer end-products.2: Flavours End-Use Market Figure 1.14 Figure 1. with Western Europe representing about 29% of the world market and Japan with 12%.3: Fragrance End-Use Market These end-use markets are typical of first world markets.6 . Figure 1.

2.3 21 10.6 56.6 107. which accounts for the rest of the market consumption.3 South African Flavour and Fragrance Industry The South African market in 1999 was worth a total of $107.1 3.5 3.1: Market for flavour and fragrance in South Africa 1999-2004 End-use Flavours Beverages Diary Snacks/ Savoury/ Convenience Bakery Confectionary Meat Oral Hygeine/ pharmaceutical Others* TOTAL Growth Rate Soap/ Detergents Cosmetics/Toiletries Household cleaners Fine fragrance Others# TOTAL Growth Rate GRAND TOTAL # 1999 2004 Value ($ millions) 18.2 6.6 27. Flavour products were the largest application at about $56.1 67.4 4.7 3.6 3.2 5.2 50.1 9. aromatherapy. The market of flavour and fragrance in South Africa in 1999 and projected for 2004 is shown in the Table 1.7 9. 1.6 6.9 9.0 2.6 2.4 5.7 14.7 5. offer significant potential growth as use of the consumer products in these particular major end-use markets increase.7 24.0 6. etc. developing countries. . insecticides.2 2.3 2.4 57.0 8.3 7.1 below:8 Table 1.3 milllion.5 3.6 12.3 * Including pet food and tobacco.70% 125.15 On the other hand.7 million7. including candles.

for example linear or branched alkyl groups. Actual values for this market have not yet been reported for 2004. Within this sector. washing soap is predominantly used in the less affluent regions.3 million (R877 million at the exchange rate of R7/US $). Many of these alkoxybenzaldehydes and secondary products.3 Overview of hydroxy.3. the current emergence of the black middle class is having a positive impact on the consumption levels of flavour and fragrance containing compounds. These types of aldehydes resemble their aliphatic counterparts. Any increase in the production of aroma chemicals and essential oils in South Africa would increase the participation in the regional flavour and fragrance market. which mean that they are susceptible to further oxidation so that air must be excluded and/or stabilizers should be added during storage. Within the fragrance sector. are used in the flavour and fragrance industries. where the use of washing machines is at nominal levels.1 General In this particular project we are considering the production of alkoxybenzaldehydes of the type: and where the aromatic ring may contain further substituents. 1. the largest use is in soaps and detergents. Many cosmetics and toiletries multinational companies have located production facilities in the South Africa as the production of base for the sub-Sahara region.and alkoxybenzaldehydes 1.A.16 In S. In . The total value of the South African market was predicted to be in the order of $125. such as the corresponding hydroxybenzaldehydes and their acetal derivatives.

2. electroplating formulations. an important commercial chemical used in soaps. petroleum chemicals.1 Uses Hydroxybenzaldehydes The two isomers that represent more than 99% of the hydroxybenxaldehyde market are 2. using the Perkin reaction (aromatic aldehyde condensation)11 involves the reaction of salicyladehyde with acetic acid anhydride in the presence of sodium acetate. polymers and fibres. also known as salicylaldehyde. and its derivatives are used in applications such as agricultural chemicals. they can be used as starting materials for pharmaceuticals.and 4-hydroxybenzaldehyde [(a) and (c)].9 1.2.3. flavours and fragrances and as a brightener and levelling agent in the electroplating industry. The anticoagulant.12 can typically be prepared from 4-hydroxycoumarin.1 2-Hydroxybenzaldehyde 2-Hydroxybenzaldehyde.17 addition.5 3-Hydroxybenzaldehyde (b) is mainly used as an intermediate in the production of dyes and some pyrethroid pesticides.3. acenocoumarol (e).10 1. The synthesis of coumarin (Scheme 1.2).2 1. perfumes.3. agricultural chemicals and fertilizers. The largest use of salicylaldehyde is for the production of coumarin (d).1. .

1.18 O OH CH3 O CH3 O O + (a) CH3CO2Na O O (d) Scheme 1. Derivatives of salicyladehyde are also used in photography. various polymer applications and for metal ion removal13 (via chelating mechanisms). It has a slight aromatic odor and has a high melting point (117 oC).14 Other derivatives of this aldehyde that are generally used in the flavouring industry are 3-ethoxy-4-hydroxy-benzaldehyde (g).3. sublimes between 110 and 120 oC.81 g per 100 g water at 18 oC). 4-Hydroxybenzaldehyde is commonly used in food adulteration.5 1. being utilized to replace natural vanilla. as well as sweet vanilla. and can be used to form ultraviolet absorbing products upon interaction with compounds containing active ethylene groups.2.2: Coumarin Synthesis Salicyladehyde itself has preservative and antibacterial properties. and is sparingly soluble in water (0. 3-methoxy-3-hydroxybenzaldehyde (vanillin) (h) (as dry vanilla .2 4-Hydroxybenzaldehyde 4-Hydroxybenzaldehyde is a colourless to tan-coloured solid that occurs in nature in small amounts in some plants.

and 4-(4-hydroxy-3-methoxyphenyl)-3-buten-2-one (l) (with a sweet.19 chocolate)15. 4-hydroxy-3-methoxybenzyl alcohol (k) (as mild sweet balsamic vanilla). (j) (as heavy sweet vanillan nutmeg). 4-acetyloxy-3-hydroxybenzaldehyde (i) (with a mild balsamic.3: Synthesis of Anisaldehyde . and is made in a simple one-step synthesis by reaction of 4hydroxybenzaldehyde with methyl chloride (Scheme 1. 4-anisaldehyde (n). but rather as an intermediate in the synthesis of some fragrances. 4-hydroxybenzaldehyde is not used as a fragrance. O O CH3Cl 3 OH (m) O (n) CH3 Scheme 1. floral odour).16 Despite an agreeable aromatic odor. A methyl ether derivative. 4-isobutoxy-3-methoxybenzaldehyde.3). is a commercially important fragrance. warm and long lasting odor).

4).4: Synthesis of Raspberry Ketone 4-Hydroxybenzaldehyde is widely used as a starting material in the production of a variety of other useful products by various sectors in the chemical industry. 4-(4-hydroxyphenlyl)butanone (o) or raspberry ketone.5).5 O CH3 CH3 CH3COCH3 OH (m) O (o) CH3 Scheme 1. a type of polymer currently used in flame retardant fabrics or space craft parts which need to withstand extreme temperatures (Scheme 1. is prepared from 4-hydroxybenzaldehyde and acetone (Scheme 1. The PBI material manufactured from 4-hydroxybenzaldehyde imparts desirable handling characteristics to the material.20 Another fragrance.17 . along with thermal resistance. One of its more recent uses is in the manufacture of a new range of polybenzimidazoles (PBI’s).

21 Scheme 1.5: Manufacture of a new range of polybenzimidazoles Other polymeric applications include the improvement of the resiliency and dyeability of poly (vinyl alcohol) fibres by incorporating 4-hydroxybenzaldehyde in .

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the fibre itself. The hydroxyl group provide sites in the fibre for the formation of stable Mannich bases attached to the backbone of the polymer.5 The dye industry utilizes 4-hydroxybenzaldehyde in the synthesis of Merocyanine Dye. These dyes are known to display different colours, depending entirely on the solvent used. A single dye can therefore be purple, blue, green, red, green, orange or yellow, the colour being determined by the polarity and extent of hydrogen bonding in the medium. Its synthesis involves an Aldol condensation between 4-hydroxybenzaldehyde and a stabilized 1,4-dimethyl pyridinium carbocation (p) (Scheme 1.6). The resulting alcohol is dehydrated and deprotonated to form 1-methyl-4[(oxycyclohexadienylidine)-ethyllidene]-1,4dihydropyridine (q).18

Scheme 1.6: Aldol condensation between 4-hydroxybenzaldehyde and a stabilized 1,4-dimethyl pyridinium carbocation 4-Hydroxybenzaldehyde is often used as a convenient intermediate in the pharmaceutical industry. Examples include the Strecker synthesis,19 a special case of the Mannich reaction, to prepare alpha amino nitriles. 4Hydroxybenzaldehyde is treated with NaCN and NH4Cl, and after acid hydrolysis of the resulting cyano group, this affords 2-(4-hydroxyphenyl) glycine (r) (Scheme 1.7).5 Compound (r) is an important commercial intermediate in the preparation of semi synthetic penicillin, amoxicillin (s).

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NH2

O

O

NACN, NH4CN H3O
OH (m) OH (r)

Scheme 1.7: The Mannich reaction

Many cephalosporin-type antibiotics (t) can also be made by this route.20 Another pharmaceutical, trimethobenzamide (u), an antiemetic, is also prepared from 4hydroxybenzaldehyde and 2-(4-hydroxyphenyl) glycine.21,22
O H2N NH O O O S CH3 CH3 OH OH (t) H2N N R

O O O R

OH

(s)

O H3C O NH H3C O O CH3 (u) O H3C N CH3

4-Hydroxybenzaldehyde finds many applications in the agricultural industry. Mostly used as an intermediate in the synthesis of a variety of agricultural products, 4-hydroxybenzaldehyde is the most important isomer in the sector.

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Herbicides like 3,5-dihalo-4-hydroxybenzonitriles are prepared via halogenation of 4-hydroxybenzaldehyde, followed by nitrile substitution for the aldehyde group. The most important herbicides of this type are bromoxynil (v) and ioxynil (w) although several other hydrazone derivatives also display herbicidal properties.5

1.3.2.2

4-Hydroxyacetophenone (x) is mainly used for the preparation of

4-Hydroxyacetophenone

pharmaceuticals. Amongst these is Salbutamol/Albuterol (y), the general bronchodilator used in most ventilators, and Atenolol (z), a β adrenergic blocking agent.23

CHCl 3 NaOH. despite the potential advantage of regioselectivecontrol. Production routes from cresols (Scheme 1. Dow Chemical Company from (USA) produces using 4an 2hydroxybenzaldehyde from phenol using the Reimer-Tiemann reaction.8) have enjoyed most commercial success.4.25 1. CH2 O Saligenin glyoxilic acid glyoxilic acid condensation OH OH OH [O] O R OH O R OH OH H2O acid O OH (a) O OH [O] HO O (aa) a) electrochemical b)catalytic OH O (m) .1 Introduction The main synthetic routes to hydroxybenzaldehydes are currently based on either phenol or cresol. At present. The phenol-based routes (Scheme 1.4 Overview of Synthetic Routes to Hydroxybenzaldehyde 1.24 OH Cl OH (USA) produces hydroxybenzaldehyde from phenol using a process based on the Saligenin H2O O Cl Vilsmeier AlCl 3. produces route. BASF (Germany) 4-hydroxybenzaldehyde and Rhône-Poulenc p-cresol electrochemical reaction.9) have had only limited success. HC(OR) 3 Reimer-Tiemann NaOH.

4.9: 4-Hydroxybenzaldehyde .Routes from Phenol Scheme 1.10).4.8: 4-Hydroxybenzaldehyde .Routes from Cresol 1.26 Scheme 1.2 Routes from Phenol 1.2. .1 The Reimer-Tiemann reaction In this case phenol is reacted with chloroform in aqueous alkali to obtain an mixture of 2-hydroxybenzaldehde and 4-hydroxybenzaldehyde through hydrolysis of the resultant benzal chlorides (Scheme 1.

23 Distillation is normally used as a method of isolation.25 Other than low yields.26 Dow Chemicals modified the reaction by adding 10 -75 % of aqueous methanol with the hope of improving the selectivity to 4-hydroxybenzaldehyde. and the expense of recovery and recyle of unreacted chloroform and phenol. with a typical isomer ratio of 85 :15 in favour of 2-hydroxybenzaldehyde. due to the sublimation of 4-hydroxybenzaldehyde. this reaction suffer from other drawbacks such as the need for an excess of chloroform over phenol.10: Reimer-Tiemann Reaction .27 In most cases the aldehyde yield is moderately low. but not without difficulty. However the difficulties of isolation and recovering the unreacted phenol still remains and the conversion is still low.27 + OH O Na - Cl Cl O Na - + CHCl3. NaOH + (a) Cl Cl OH O OH O Na - + O Na O - + + O HCl + O (j) (m) Scheme 1.

Yields reported in the literature are about 85 % . so it can be easily hydrolysed to the desired aldehyde. and 4-hydroxybenzaldehydes is claimed to be about 50/50. The use of various base and water loadings. phenol is reacted with formaldehyde in the presence of aqueous base (ionic protection of the phonoxy group) to afford both isomers of the sodium salt of hydroxybenzyl alcohol (Scheme 1.5 1. N-dimethylformamide in benzene.28 Various reports in the literature suggests various approaches for improving the selectivity of 2-hydroxybenzaldehde.2 Vilsmeier Aldehyde Synthesis This method for the formation of hydroxybenzaldehydes (see scheme 7) used to be the preferred industrial method. Friedel-Craft catalysts such as aluminium chloride (instead of phosphorus oxychloride) and trialkyl orthoformate can also be used when performing these reactions. The resulting acetal is very unstable under acidic conditions.11.4. and is applicable to activated substrates such as amines and phenols. including: • • • • The addition of surfactants under anhydrous reaction conditions. This reaction uses disubstituted formamides in the presence of phosphorus oxychloride. Regioselectivity to the 2-.28. The ratio of 2hydroxybenzaldehyde to 4-hydroxybenzaldehyde for this process is reported to be typically 7.2. The use of aprotic solvent catalysts like N. (ab) and (ac)). The highest conversion reported (96 % with a selectivity of 63%) was reported for a process operated by Simutomo Chemical Company.3 Saligenin Reaction The saligenin name was derived from the very first step of the reaction.4. In this step. Use of phase transfer catalysts etc.8:1. formation of 2-hydroxybenzyl alcohol or saligenin.29 1.2.

Other mediators such as boron.4. Mandelic acid can in turn be oxidized to 4-hydroxybenzaldehyde in alcoholic medium using a copper catalyst and air.30 However the use of platinum. bismuth. NaOH + (ac) OH [O] - (ab) OH O OH O - Na + O Na + neutralize O + O + O (j) (m) Scheme 1. or activated carbon as catalysts is quite common for this conversion. Literature reported yields are . tellurium.32 - OH O Na - + O Na+ OH + CH2O aq. palladium. cerium.2. silver or tin to increase catalyst activity and stability has also been claimed. indium.4 Glyoxilic Acid Condensation Condensation of phenol with glyoxilic acid affords mandelic acid (aa) with a yield of almost 77 %.31.5. cadmium.11: Saligenin Reaction 1. lead. lanthanum.23 The catalytic air oxidation of the intermediate benzyl alcohol phenolates affords both hydroxybenzaldehyde isomers and it can be performed without a catalyst in an alkaline medium between 25 and 50 oC.29 and the ratio of 2-hydroxybenzyl alcohol to 4-hydroxybenzyl alcohol can be controlled by optimisation.

4.3.13: Side chain halogenation .34 OH O Na+ - + HO O (aa) OH NaOH H2O + O CO3 2.12).13).23 OH CH3 OH OH Cl Cl 2 Cl2 .33 1. Deprotection is by simple hydrolysis.12: Electrochemical Oxidation of Mandelic Acid The reaction is performed under strong basic conditions and at temperatures between 30 and 60 oC.30 about 88%. leading to a 90% yield (Scheme 1.3 Routes from Cresols 1.+ 4H+ + 2e- Scheme 1.2 HCl O Scheme 1. Esterification with an inorganic or organic acid chloride is used to protect the phenolic group prior to chlorination.4.33 The disodium salt of mandelic acid can also be oxidized electrochemically using carbon felt electrodes.1 Side-Chain Halogenation Side-chain chlorination of cresol can be carried out to form the unstable dichloromethane intermediate (ad) which can be hydrolysed to the respective hydroxybenzaldehyde (Scheme 1.2 HCl (ad) + H2O .

The reports on p-cresol oxidations focuses mostly on the catalytic air oxidation in alkaline media. The most widely reported solvent for such oxidation reactions is methanol and the most widely used catalysts are based on cobalt.36 More than two and a half times the molar equivalent of base to cresol is required for reasonably successful oxidations. including: ! ! ! Slow reaction rates.31 Chlorination is generally not very selective and a variety of ring chlorinated byproducts often results. recovery of by-product hydrochloric acid gas. High explosivity of methanol air mixtures. The following potential routes have been investigated: • • Oxidation under basic conditions.37 Conversions are typically in the order of 90% with selectivities to the aldehyde generally in the order of 80 – 85%. .5. as well as separation of the large amounts of by-products.3. and Catalyst deactivation which results from the formation of hydroxylbridged cobalt complexes in aqueous media. The methods based on the alkaline methanolic air oxidation of cresols in the presence of cobalt salts suffer several disadvantages.35 Disposal of the chlorinated waste-streams.2 Catalytic Air Oxidation A significant amount of research on catalytic air oxidation of cresol to hydroxybenzaldehyde has been reported. 1. 4-Hydroxybenzyl alcohol and 4hydroxybenzyl ether sodium salts are intermediates in the above process. Halogenations are in general being phased out due to environmental regulation and legislations globally. are expensive and difficult.26.4. Oxidation under acidic conditions. but is not currently utilized on commercial scale.

38. and also much more efficient with isolated yields of 4-hydroxybenzaldehyde >98% after recovery and recycling of reaction intermediates. followed by crystallization of the phenolate salt of 4-hydroxybenzaldehyde. several modifications to the method have been claimed. chromium. Selective extraction with 3-methyl-2-butanone has been claimed to remove 4-hydroxybenzaldehyde at pH 10. Initial neutralization of the reaction mixture results in the co-precipitation of 4-hydroxybenzaldehyde. the use of activated carbon and three-dimensional silicate supports for oxidation catalysts. the use cobalt. substantially lower molar equivalents of base (even as low as 1:1) were found to be effective during these oxidations. and the use of platinum metal group (PMG) catalysts. In addition. In contrast to the oxidation of p-cresol in alkaline methanolic solutions. The isolation of 4-hydroxybenzaldehyde from oxidation mixtures is most commonly achieved by the addition of water to the mixture. neutral by-products and unreacted substrate.26 . nickel salts as catalysts in the presence of easily removed amines. and 4-hydroxybenzaldehyde at pH 5 have also been reported. These procedures were reportedly much safer than similar oxidations in alkaline methanolic solutions. the use of chelated iron or manganese catalysts together with various co-catalysts. filtration of the catalyst or hydrated metal species.32 The very first patent on the air oxidation of p-cresol and its derivatives in alkaline methanolic medium using cobalt based catalysis was filed in 1979 by the Sumitomo Chemical Company. including the use of water.39 Since this particular report. researchers from the Port Elizabeth Technikon reported the oxidation of pcresol 40 in an 80:20 ethylene glycol:water mixture using a copper(II)-cobalt(III) spinel catalyst. the use of and inert organic co-solvent. while selective crystallization of by-products at pH 10. the use of applied oxygen pressure. manganese.

HX O (m) Scheme 1.3. Typical yields are about 75% 4-hydroxybenzaldehyde at 70% substrate conversion. which is formed in significants amounts at high substrate conversions (at least 70%). Reported yields approach 98%. 4-hydroxybenzyl acetate.3 Electochemical Oxidation The German company BASF41 have been operating a process for the production of 4-hydroxybenzaldehyde based on a 4-electron oxidation of the protected cresol. Side-products include 4-hydroxybenzyl alcohol. The electrochemical .14: Electrochemical oxidation of 4-tert-butoxytoluene 4-Hydroxybenzaldehyde is liberated in a separate step through treatment with an aqueous mineral acid. However. Deactivation of the very expensive PMG catalysts are partially relieved by the use of transition metal promoters.33 The oxidation of cresol in acidic medium (carboxylic acid) has been studied in lesser detail as indicated by the number of published reports in the literature compared to the oxidation in alkaline methanolic solutions. regeneration of such catalyst could be problematic and therefore costly.14). and 4-hydroxybenzoic acid.4. 1.4 eR CH3 (ae) O (af) O R aq. These oxidations are generally performed in dilute solutions. and suffer from the formation of dimeric polymeric side products. when using supported PMG catalysts. 4-tert-butoxytoluene (ae) in methanol (Scheme 1. The most common solvent employed for these oxidations are mixtures of acetic acid and water. affording the dimethoxymethyl derivative (af) H3C CH3 CH3 O H3C O CH3 CH3 OH 2ROH .

the protection and deprotection of the phenolic group. .e..34 oxidation of p-cresol as described above requires two additional steps i.

Unless otherwise stated. together with their sources and grades are listed in Table 2. and electrochemical oxidation procedures. Table 2.1.xH2O Co(CH3COO)2.4H2O Cu(CH3COO)2.6H2O Minema sulfate Ammonium nitrate NH4NO3) Saarchem Barium chloride BaCl2.7% CP CP CP CP CP CP CP CP CP CP AR AR AR HP Ammonium ferrous Fe(NH4)2(SO4)2.1 Reagents for synthesis All reagents used in alkylation. all reagents were used as received.3H2O Cerium sulfate Cerium(II)acetate Chromium(III) chloride Cobalt(II) acetate Copper(II) acetate Dichloromethane Diethyl Ether Di-oxygen CeSO4 Ce(CH3COO)2.H2O Aldrich/Merck Benzene sulfonic acid C6H5 SO3 Na sodium salt Ceric ammonium nitrate (NH4)2Ce(NO3)6 Cerium(III) carbonate Ce2(CO3)3.1.35 CHAPTER 2 EXPERIMENTAL 2.2H2O Merck .1 Reagents used for synthesis and oxidations Chemical Name 3-tert-Butyl-4methoxytoluene 3-tert-Butylchloride 4-Methoxytoluene Acetone Aluminium Oxide Ammonium bromide Chemical Formula C12H18O C4H9Cl C8H10O C3H6O Al2O3 NH4Br Source Synthesized Saarchem Merck Saarchem Merck M&B Grade A CP CP AR AR CP >98.1 Materials 2. catalytic air oxidation.H2O CH2Cl2 C2H5OC2H5 O2 Aldrich Fluka Aldrich Aldrich/Merck Aldrich Aldrich Mallinckrodt SMM Instruments Saarchem Air products [CrCl2(H2O)4]Cl.

36

Chemical Name Ethyl acetate Ferrous sulfate Glacial Acetic acid Hexane Hydrobromic acid Iso-Butyric acid
B

Chemical Formula CH3CH2OCOCH3 FeSO4 CH3COOH CH3(CH2)4CH3 HBr (CH3)2CHCOOH MgSO4 Mn(CH3COO)2.4H2O CH4O3S CH3OH CH3CH2CH2COOH C6H5NO2 CH3(CH2)3COOH CH3(CH2)3COOH HP3O4 KBr K2CO3 KCl CH3CH2COOH NaCO3 NaOH H2SO4 CH(OCH3)3

Source Saarchem Saarchem Saarchem Saarchem BDH ICN Biomedicas Saarchem Aldrich Aldrich Saarchem Merck Saarchem Ega-Chemie Saarchem Saarchem Skychem BDH Aldrich/Merck Saarchem Saarchem Aldrich Saarchem Skychem Aldrich

Grade A AR CP AR AR AR CP CP CP CP AR Grade A AR CP CP AR CP CP CP AR AR CP CP CP CP

Magnesium Sulfate (Anh) Manganese(II)acetate Methane sulfonic acid Methanol n-Butyric acid Nitrobenzene Octanoic acid Pentanoic acid Petroleum Ether Phosphoric acid Potassium bromide Potassium carbonate Potassium chloride Propanoic acid Sodium carbonate Sodium hydroxide Sulfuric acid Trimethyl othoformate
A

-AR = Analytical reagent, CP = Chemically pure, HPLC = HPLC grade, HP =

High purity, B = (HBr concetraction = 45 % w/v)

37

2.1.2 Reagents for Analysis
2.1.2.1 Reagents for HPLC analysis Additional reagents used in HPLC and GC analysis, together with their sources and respective grades, are listed in Table 2.2 and Table 2.3 and were used as received. Table 2.2 Reagents for HPLC analysis Chemical Name 4-Methoxytoluene Acetonitrile Methanol 3-tert-Butyl-4methoxy toluene 3-tert-Butyl-4methoxy benzyl dimethyl acetal
A

Chemical Formula C8H10O CH3CN CH3OH C12H18O C14O3H22

Source Merck BDH Saarchem Synthesized Synthesized

Grade A AR HPLC HPLC CP CP

-AR = Analytical reagent, CP = Chemically pure, HPLC = HPLC grade

Table 2.3 Reagents used as GC standards. Chemical Name 4-Methylanisole p-Anisaldehyde 4-Methoxybenzyl alcohol p-Anisic acid Nitrobenzene
A

Chemical Formula CH3C6H4OCH3 CH3OC6H4CHO CH3OC6H4CH2OH CH3OC6H4COOH C6h5NO2

Source Merck Aldrich Aldrich Aldrich Saarchem

Grade A CP CP CP CP AR

-AR = Analytical reagent, CP = Chemically pure, HPLC = HPLC grade

38

2.2 SYNTHETIC PROCEDURES 2.2.1 Catalytic air oxidation studies A 250 cm3 three-necked round bottom flask equipped with a double surface reflux condenser was used for all the oxidation experiments. Oxygen was delivered through a bent tip pasteur pipette through the side neck of the flask. Fine control of oxygen flow was maintained with a needle valve connected to the laboratory oxygen supply. The reaction temperature was controlled by immersing the reaction flask in an oil bath equipped with an external stirrer on a magnetic stirrer hotplate and closely monitoring the oil temperature. The external stirrer provided circulation to the oil, and ensured even distribution of heat from the hotplate. All the starting materials, except the substrate and acid solvent, were weighed directly into the reaction flask. The required volume of solvent was added with a burette. The reaction flask was allowed to equilibrate to the required temperature. The required volume of substrate was added with a bulb pipette. A sample was taken by removing an aliquot (less than 0.15 cm3) of the reaction mixture and diluting it with 3 cm3 of diethyl ether in a vial containing some anhydrous sodium sulfate and oxalic acid. The samples were analyzed by means of a GC or HPLC.

2.2.2 Synthesis of 3-tert-butyl-4-methoxytoluene 4-Methoxytoluene (100 g, 0.858135 mole) was transferred to a 500 mL reaction vessel, sulfuric acid (8.0 mL, 0.09 M) was added as a catalyst and the mixture heated to reflux. Tert-butyl chloride (63.5 g, 0.648177mole) was added drop-wise with a dropping funnel over a period of 1 hour while stirring at a rate of 800 rpm. The mixture was then refluxed for 5 hours in an oil bath at 70 oC. Scheme 2.1 depicts the Friedel-Craft alkylation process.

NMR analysis gave: NMR (H1. ArCH3). s. The following fragmentation patern was obtained from the GC-MS: (Mz = 178 (M+). while the methyl group shows no interaction with any of these functional groups. 2. 4 (3H.60 oC The sample was analysed by GC-MS. 7. 1. proton NMR spectrometry.1 Friedal-Craft alkylation of 4-methylanisole After 5 hours the mixture was allowed to cool and extracted with ethyl acetate (3 x 150 mL). Ar C(CH3)) From the noesy diagrams Figure 2. 163 (Mz – 15). s.39 Scheme 2. s. and cosy and noesy analysis to confirm the structure of the resulting isomer. 148 (Mz – 31). The yield of of the desired isomer was 56 % based on GC-MS area percentage.85 (1H.50 oC and the second fraction containing 3-tert-butyl-4methoxytoluene at 9 torr in the temperature range 55 . Two fractions were collected. 91 (Mz – 31 – 57).1 it can be seen that there is a definite interaction between the t-butyl group and the methoxy functional group.15(2H. and once with 400 mL of a 10 % sodium carbonate solution. ArOCH3).4 (3H. Vaccum distillation was used to separate the two isomers. d. d. and the ethyl acetate extracts washed with 3 x 100 mL distilled water. Ar). . ppm) (CDCl3). 6. Samples were dried with anhydrous magnesium sulfate and analysed by GC-MS.5 (9H. 105 (Mz – 15 – 57). the first containing 4-methoxytoluene at a pressure of 9 torr in the temperature range 45 . Ar).

5. was found to be 98 %. it can be seen that there is a para hydrogen arrangement marked H1 and H3 at J = 1.8. The purity of 3-tert-butyl-4-methoxytoluene.1 Noesy diagrams If one studies the cosy diagram (Figure 2.2) and in particular a contour cut over the aromatic ring. These measurements together with the Noesy diagram confirm the isolated product as the 3-tert-butyl-4-methoxytoluene isomer. determined using an HPLC internal standard method.40 Figure 2. . There is also an ortho hydrogen arrangement marked H1 and H2 at J = 5.

a heating mantle.43.min-1 maximum flow rate). which is based on the filter press or plate and frame arrangement.3 Direct electrochemical synthesis of 3-tert-butyl-4-methoxybenzaldehyde42.44 An ICI electrochemical processing laboratory package unit (Figure 2.2. which was connected . an Iwaki MD-30F impeller pump. At the core of the process unit lays the FM-01 flow cell.2 Cosy diagrams 2.3) was used for larger-scale electrochemical oxidation procedures. the FM01-LC flow cell. precision glass flow indicator (2 L. an inlet tube from the electrolysis cell and an outlet tube to the impeller pump. The pump forced the liquid through the flow indicator into the flow cell.41 Figure 2. The electrochemical setup consists of a four neck 500 mL round bottom flask. The flask was fitted with a condenser in order to prevent a pressure build-up in the system in case of gas formation in the cell. and a Lorin SCT 20-30 galvanostat.

The flow cell outlet fed back into the round bottom flask in order to complete the loop. Apparatus Anode Cathode Current density Electrolysis Temperature Time : Undivided cell with 2 electrodes : Graphite : Graphite : 1.5 A/dm2 : Constant at 40 oC : 2:30 hr .3: Batch recirculation flow cell for scale-up Electrolysis was carried out in the constant current mode using graphite electrodes as cathode and anode. Figure 2.42 to the galvanostat.

The reaction was stopped after 2:30 hours.2. NaSO3C6H5 (10 g. .4 Indirect electrochemical synthesis of 3-t-butyl-4-methoxybenzaldehyde using Ce(IV)45. The acetal was hydrolysed to the corresponding aldehyde in a 10 % sulfuric acid with stirring for 1 hour.4. The ethyl acetate washings was combined with the filtrate and vacuum distilled. The crude product was then recrystallized with petroleum ether (30 – 60 oC) 2. Figure 2.05556 mol) was added as a supporting electrolyte and 500 mL of methanol as solvent. Once the reaction mixture has reached the desired reaction temperature.084142 mol) was weighed and transferred to the 3 neck round bottom flask.1 Cyclic voltammogram studies Preliminary investigations were performed on a CV-50W instrument using a Pt – disk (5 mm) electrode versus a Ag/Ag+ reference electrode to study the oxidation and reduction system of cerium (0. The mixture was heated to 40 oC by adjusting the temperature of the heating fluid in the circulator bath while the mixture was pumped through the system at a flow rate of 0. The reaction mixture was then transferred to a distillation flask together with 200 mL of methanol that was used for rinsing the reservoir and electrochemical cell.28 g) was filtered and washed with 2x100 mL of ethyl acetate. Dried and solvent evaporated on a rotator evaporator. The 3-tert-4-methoxybenzaldehyde was then extracted from the aqueous layer with ethyl acetate 3 x 25 mL.2.5 A dm-2.05 mM) in methanesulfonic acid (6 M). the galvanostat was switched on and the current adjusted to provide a current density of 1. 0.46. 0.43 3-Tert-butyl-4-methoxytoluene (15 g.8 L h-1.47 2.4 shows the cyclic voltammogram for this system. The methanol was distilled (recovered methanol was 700 mL) and the supporting electrolyte that precipitated (9.

4: Cyclic voltammegram for cerium (0.00E-05 Potential (V) 200 400 600 800 20 mV s-1 1000 1200 1400 1600 -1 1800 2000 50 mV s 100 mV s-1 Figure 2. From Figure 2.00E-05 -6.00E-05 0.00E-05 -8.5: Effect of scan rates on the quasi-reversible system of cerium methanesulfonate.00E-05 2.00E-05 -8.00E+00 -2.20E-04 1.00E-04 8.00E-05 Potential (V) 200 400 600 800 1000 1200 1400 1600 1800 2000 Figure 2.00E-05 2. A quasi-reversible system was obtained with an oxidation state of CeIII to CeIV at 1.00E+00 -2.44 1. 1.00E-05 4.00E-05 0 -4.65 V which compares well with literature data48.5 it can be seen that the current increases with increasing scan rates.00E-05 4. .05 mM) in a methanesulfonic acid solution (6 M) using a Pt-disk (5 mm) electrode.00E-04 8.20E-04 1.00E-05 Current (mA 6.00E-05 -6.00E-05 0 -4.00E-05 0.00E-05 Current (mA 6.

150 g. To this precipitate a solution of saturated barium chloride was added to ensure complete removal of sulfate ions as barium sulfate. 2 M.3 Synthesis of Ce(IV) methanesulfonate solution Portions of the dry yellow powder (5. 2.2 Synthesis of Ce(III) Carbonate A solution of potassium carbonate (8.2.4 3-Tert-butyl-4-methoxytoluene oxidation using Ce(IV) methane-sulfonate The Ce(IV) solutions prepared as described above was used to oxidize 3-tertbutyl-4-methoxytoluene to 3-tert-butyl-4-methoxybenzaldehyde by stirring 3-tertbutyl-4-methoxytoluene (dissolved in various solvents) with 50 mL of the Ce(IV) solution at temperatures ranging from 20 – 80 oC for 6 hours. The resultant yellow powder was then dried in air in an oven at 50 oC. 0. 2. These solutions were electrochemically oxidized using a platinum basket as the anode and a platinum electrode as the cathode at 1 A for six hours to produce solutions of Ce(IV) methanesulfonate. 2.6502 g.4.093445 mol) in 48 mL of water was added with vigorous stirring to a solution of ceric sulfate (10.01119 moles) was dissolved into 45 mL methane sulfonic acid solutions of varying concentrations of acid. and washed with large amount of water to remove the barium sulfate and potassium chloride. 4 M. A pale yellow precipitate of Ce(III)carbonate was produced. The actual concentration of Ce(IV) was determined by titrating against ferrous ammonium sulfate using ferroin as indicator.4. 0.2.2. The precipitate was collected with vacuum filtration.45 This studies show the ease of oxidizing Ce(VI) in a methanesulfonic acid medium. . 6 M and 8 M to produce Ce(III) methanesulfonate solutions.4.030668 mol) in 40 mL of water. viz. 0.1892g.

This slurry was collected.2. the methane sulfonic acid concentration adjusted to 6M and oxidised to cerium(IV) methane sulfonate as described in §2.2. the spent Ce(III) methansulfonate.2. The actual concentration of Ce(IV) in these solutions were determined by titrating the solution against ferrous ammonium sulfate using ferroin indicator and the substrate loading was calculated to correspond to a substrate:Ce(IV) mole ratio of 1:4. 150 mL in volume. The spent cerium(III) salts was recovered by evaporating the bulk of the methanol to allow precipitation of the cerium(III) salts.3. filtering. This solution was oxidized using a platinum basket as the anode and a platinum electrode as the cathode at 1 A for six hours.6 After Recycling of Ce (IV) in methanesufonic acid oxidation of 3-tert-butyl-4-methoxytoluene using cerium(IV) methansulfonate. equipped with a heating jacket and connected to a Labcon circulator in order to effect either heating or cooling. The mixture was stirred at 30 oC for 30 minutes and extracted with 2 x 50 mL dichloromethane and washed with 2 x 50 mL deionised water. The solution was used as described as for § 2.46 2. and drying.4. Samples were withdrawn from the reaction flask and analysed by either HPLC or GC.9567 g.7 Oxidations using cerium(IV) ammonium nitrate A solution of ceric ammonium nitrate (8. appears as a white slurry in the aqueous phase.4.5 Preparation of cerium(IV) methanesulfonate from commercial Ce2(CO3)3 A commercial sample of (57.2 above.1247966mol) cerium(III) carbonate (Aldrich) was dissolved in 500 mL of a 6 M methane sulfonic acid solution. 2.49 .2.44015g. 0. 0. 2. The concentration of Ce (IV) was determined by titrating against ferrous ammonium sulfate using ferroin as indicator.01634 mol) in 50 mL of methanol was transferred of a double walled reactor flask.2.

The cell consists of a double-walled reactor flask. A constant current of 0.8 Direct electrolysis in an undivided electrochemical cell The electrochemical cell shown in Figure 2. thermometer. depending on the moles of Cerium. ammonium nitrate (0. equipped with a heating jacket.47 2.2. which was connected to a Labcon circulator in order to affect either heating or cooling.4 was used for direct electrochemical oxidation studies.2.00749 mol) in 30 mL of methanol added as supporting electrolyte. 0.50 2. controlled by a Lodestar Instrument general purpose galvanostat. 150 mL in volume.6g. to the mixture as before. and a condenser. The concentration was determined by titrating against ferrous ammonium sulfate using ferroin indicator. The electrolysis was always carried out under constant current conditions. The top of the reaction flask was designed with a screw top and quick fit adapters for the insertion of electrodes. and the solution electrolysed using two platinum electrodes in a divided cell.2:00 hours till the concentration of Ce(IV) was constant.1 Recycling of cerium ammonium nitrate Recovered cerium salts from oxidation reactions using cerium(IV) ammonium nitrate were dissolved in 50 mL of methanol.7. .3 A at a cell potential of 9 -10 volts was passed through the cell for 1:30 . These solutions were used for further oxidation reactions by adding the required amount of substrate.

1 Gas Chromatography – Mass Spectrometry Gas chromatography-mass spectrometry analyses were performed on a Thermo Finning GC-MS fitted with a mass selective detector.3 ANALYTICAL TECHNIQUES Several analytical procedures were employed for the analysis of substrates. The GC-MS was connected to a PC equipped with Excalibur software.48 Figure 2.3. products and supporting electrolytes.25 cm thickness). intermediates. Table 2.3 below summarizes the GC-MS conditions used for analyses.4: Direct electrochemical oxidation setup 2.3. .25mm ID x 0. version 1. a RTX 35ms column (length 30m x 0. 2.

Nitrobenzene was used as internal standard and the internal standard method was used for all quantitative work.5.49 Table 2.3.2 High Pressure Liquid Chromatography HPLC analyses were performed on a Hewlett Packard HP1100 HPLC system equipped with a UV-detector and connected to a PC equipped with a Hewlett Packard Chemstation. version 8.4 GC-MS conditions 70 OC 5 min 10 OC/min 210 OC 5 min 250 OC 60 ml/min Helium at constant flow 24 min 30 – 350 amu Initial column temperature Initial column hold time Heating rate Final column temperature Final column hold time Injector temperature Split flow Carrier gas Run time MS-mass range 2. Response factors for the components of interest were determined by means of three calibration injections with known masses of standards and internal standard prior to analysis. Relative standard deviations for the three standard injections were typically within the range 0.2 – 0.5%.03. The HPLC conditions used are shown in Table 2. .

50 Table 2. The solvent used for conductivity measurements was dried before use by the addition of a water scavenger such as trimethyl orthoformate.3 Conductivity Studies A Metrohm 660 conductivity meter.4 Cyclic voltammetry Cyclic voltammetry was performed on a BAS CV-50 system consisting of the electrochemical cell. a Pt wire auxiliary electrode and a non-aqueous Ag/AgCl reference electrode linked to a PC. Acetonitrile was used as solvent in CV studies of the reaction intermediates since methanol started to .5 mol dm-3 in methanol at 22oC. so as to determine their oxidation potentials.7V at a scan rate of 100 mV s-1 and sensitivity of 1 mA V-1.3. equipped with two platinum black electrodes.3.986 cm-1. The potential of the working electrode was scanned over a range of 0 . The cell constant was determined to be 0. The conductivity of a specific electrolyte was measured over a concentration range of 0.5 HPLC conditions 25 µL µBondpak C18 (3. Cyclic voltammograms were recorded for the substrate.2. was used to measure the conductivity and resistance of solutions containing substrates and supporting electrolytes. intermediates and final products.9x300 mm) (Waters) 280 nm 1 cm 3 min -1 MeCN : H2O buffered to pH = 3 with H3PO4 50 : 50 Injector Volume Column Wavelength Flow rate Mobile Phase Mobile phase composition 2. 2.1 -0. The supporting electrolytes were used as received. equipped with Pt and glassy carbon working electrodes.

6 UV/Visible Spectrophotometry The optimum UV absorbance wavelength of samples for HPLC analyses was determined with the aid of Beckman DU® 7500 double beam UV/Visible spectrophotometer with Beckman DU series 7000 software. 2. performed on a Metrohm 684 KF Coulometer.5 Differential Scanning Calorimetry DSC analysis was performed on Mettler Toledo DSC 820 and integrations performed using Stare software in order to determine the purity and melting point of the synthesized standards as well as their decomposition temperatures.51 oxidize at potentials lower than that of the substrate.3.3. A quartz sample cell (cuvette) was used with samples dissolved in acetonitrile as solvent 2.3. 2.8 Coulometric Analysis Water in acetic solvent was determined by coulometric analysis. Data transfer and further manipulation of data was achieved using a personal computer equipped with PC Plus software.9 NMR Spectroscopy Proton NMR spectra were recorded on a Varian EM 360 A (300 MHz) spectrometer. 2.51.52 Methanol was used as solvent for CV work dealing with different electrolytes. 2. The sample was placed in an aluminium sample pan (working range up to 400 oC) and sealed in a press. .3.7 pH Determinations An Inlab level 1 digital pH meter with a WTW Sentix single glass pH electrode was used for all pH measurements.3.

3.52 2.10 Fourier Transform Infrared Spectroscopy Infra red spectra were recorded on a Bruker Tensor 27 FTIR spectrophotometer connected to a personal computer. All samples were analyzed using KBr discs. equipped with Spectra file software. .

The direct electrochemical oxidation of the methoxytoluene. The routes that were evaluated through bench scale synthesis studies were: • • • The catalytic air oxidation of the methoxytoluene.1 General As discussed earlier.55. and The indirect electrochemical oxidation of the methoxytoluene. 3.1 Catalytic Air Oxidation 3. Studies on the partial air oxidation of substituted methyl phenols to phenolic aldehydes has been reported in considerable detail in the literature.54 followed by oxidation of the resultant p-hydroxymandelic acid.56. or from cresols or their alkyl ether derivatives by oxidation of the methyl group. Despite the disadvantage of the higher cost of cresol feed as opposed to phenol feed. p-cresol and a phenol/glyoxilic acid condensation.1. there has been considerable interest in the use of oxidative technologies for the production of hydroxy-benzaldehydes in view of the potential advantages in respect of selectivity and decreased effluent problems. hydroxy-substituted benzaldehydes (or the corresponding alkoxy-substituted benzaldehydes) may be produced starting either with phenol as substrate (and introducing the aldehyde group).53 CHAPTER 3 RESULTS AND DISCUSSION The following sections describe the results obtained for the evaluation of the various potential routes to convert alkyl-substituted methoxytoluenes selectively into the corresponding alkyl-substituted methoxybenzaldehydes. routes include an electrochemical Current commercial oxidation oxidation process53.57 . The purpose of these investigations was to be able to identify the most efficient and selective route to produce the desired benzaldehydes in high yield.

60 These procedures are supposed to be flexible enough. the phenolic group is protected by the ether group and traditional oxidation methods and catalysts may be considered for these oxidations. Deactivation of the very expensive PGM catalysts are partially relieved by the use of transition metal promoters.60 In the case of the catalytic air oxidation of methoxytoluenes. the phenolic group is conventionally protected either as the acetate (acetic anhydride and acetic acid medium58) or phenolate (alcoholic based medium59).54 To avoid the formation of polymers and tars. Regeneration of such catalysts is. to allow for the selective preparation of various oxidation products.1. using the well-known cobalt-bromide catalyst system.59. can best be described by the reaction sequence illustrated below in Scheme 3.1. most of these reactions are characterized by low yields of the desired aldehyde and the formation of further oxidized and/or oligomerization products. problematic.2 Catalytic air oxidation: Nature of the substrate Previous work in our laboratories has shown that the progress of the catalytic air oxidation of alkylbenzenes.61 However. particularly with hindered cresols. it was shown that certain supported PGM catalysts could be used to afford benzylic oxidation of a cresol without protection of the phenolic group with reasonable success. including the well known cobalt(II) acetate/bromide or cobalt(II) acetate/manganese(II) bromide catalyst system. 3. . including nucleophilic addition products and a range of coupled compounds. Recently. however. and therefore expensive. in acetic acid as reaction solvent.

The starting alkylbenzene may be transformed into oxidised products in several ways (Reactions (i). (v) and (vi)). This process (reaction (v)) is. when approximately 70% of available bromide has been converted into organic bromide (essentially the benzylic bromide). aldehyde selectivity decreases. consequently. the catalyst starts oxidising the aldehyde product at rates higher than the rate of formation of the aldehyde and. slow and requires the presence of significant quantities of Co(III) to proceed at any significant rate.55 CH2Br (ii) CHBr2 (iii) (i) CH3 (iv) (v) CHO (x) COOH (vi) (vii) (ix) CH2OH (viii) CH2OAc Scheme 3. Thus. This reaction sequence requires the catalyst system to remain in a form that contains bromide coordinated to cobalt(II). With the above in mind. but only reaction (v) leads directly to the formation of the desired aldehyde. The major route to the desired aldehyde is via reactions (vi) followed by (vii). bromide is slowly converted into an inactive form (through reactions (i) and (ii)). however. . Unfortunately. the best approach to high aldehyde selectivities would be to restrict substrate conversion to a level where the aldehyde oxidation is still slow.1 Cobalt(II)-Bromide catalysed air oxidation of alkylbenzenes.

namely initial alkylation of the aromatic ring followed by oxidation. We have studied the catalytic air oxidation of several alkylbenzenes and substituted alkylbenzenes to determine the effect of substitution on the alkylbenzene ring. To produce alkyl-substituted methoxybenzaldehydes in high yield by means of catalytic air oxidation.2 Routes to alkyl-substituted methoxybenzaldehydes via catalytic air oxidation . or initial oxidation to form the benzaldehyde (or a protected form thereof) followed by alkylation (Scheme 3. CH3 R-X CH3 OMe R [O] CHO R OMe [O] CHO OMe R-X OMe Scheme 3. the main determining factor being the rate at which the substrate is converted into the corresponding benzylic bromide. one of two routes can be followed. The reasoning behind this approach was as follows. and to evaluate the feasibility of obtaining high benzaldehyde selectivity at restricted substrate conversions.2).56 This level (of substrate conversion) will probably be different for different substrates.

reactor configuration (especially the height to diameter ratio of the reactor). It was therefore necessary to eliminate mass transfer problems by manipulating stirring and oxygen supply to the reaction vessel.62 The most important of these are dispersion of gas in the liquid (number and position of gas inlets. but also the selectivity to the desired aldehyde that could be expected from these oxidation reactions.). This can be achieved quite easily by stirring the solution magnetically at high revolutions (1000 rpm using a suitable size magnetic follower) and increasing the O2 flow rate until no effect on the reaction rate (measured as the degree of substrate conversion after a predetermined. size of air bubbles. and using a 250 mL round-bottom flask as reaction vessel. The second observation deals with the nature of the oxidation gas supplied to the reaction mixture. catalytic homogeneous air oxidations of hydrocarbons are known to be affected by a number of chemical engineering parameters which influence mass transfer in the essentially two phase (gasliquid) reaction system. and mixing method.min-1 was found to give consistent conversions of substrate. fixed reaction time – 15 minutes) is observed. a few preliminary observations should be made. such an approach is the equivalent . the selectivity achievable during the catalytic air oxidation step would be the limiting factor due to the ease of further oxidation of the desired aldehyde product. etc. In effect. Before describing and discussing the results obtained. not much control was available in terms of gas inlets. Firstly. It was therefore necessary to establish not only whether the oxidation step should come before or after the alkylation step. Of these. Under these conditions. an O2 flow rate of 30 mL. It has been claimed 63 that aldehydes could be isolated in good yields during electron transfer oxidation of alkylbenzenes under conditions of low temperature and oxygen starvation. Since all the catalytic air oxidation work described in this work was carried out in round-bottom flasks. height/diameter ratio. as well as the rate (and degree) of substitution during alkylation reactions. etc.57 The nature and extent of substitution on the ring will affect both the rate (and extent) of oxidation.

.48 g. Aliquots (0. albeit at longer reactor residence times. These oxidations were carried out using cobalt(II) acetate (0.1) were oxidised in order to establish the effect of substitution on the selectivity to the desired benzaldehydes at various substrate conversions.5 mL) of the reaction mixture were withdrawn at regular intervals and analysed by gas chromatography. glacial acetic acid (50 mL) as the reaction solvent. 1. In the first series of reactions. In this investigation the approach was rather to perform oxidations under conditions of oxygen saturation and physically restricting conversion by fixing the reaction period. Figure 3. 1.72 mmol) in a 1:1 molar ratio as the catalyst. It is argued that this approach is closer to technical reality in the attempt to increase oxidation rates and decrease reactor residence times.58 of performing the oxidation reaction to restricted conversion.1 illustrates a typical product distribution diagram (p-xylene) obtained during this investigation and illustrates the typical progression of the oxidation through the aldehyde (4-methylbenzaldehyde) to the acid (4-methyl benzoic acid).168 g.93 mmol) and NH4Br (0. a number of substituted toluenes (Table 3. a reaction temperature of 90 oC and dioxygen as the oxidation gas at a flow rate of 30 mL min-1.

6 44.99 g.1 Product distribution diagram: p-Xylene oxidation After construction of a product distribution diagram as shown below.77 mmol).40 g. Conversion (%) 20 40 Aldehyde Selectivity (%) C6H5CH3a 4-CH3C6H4CH3b 4-MeOC6H4CH3c 4-ClC6H4CH3d 2.5 24. c . 18.4-Cl2-C6H3CH3 (2.58 mmol) .6 b d 56. 18.1: Substrate Catalytic air oxidation: Nature of the substrate. 2.4-ClC6H4CH3 (2.3 44.1 29.9 45.6 35.C6H5CH3 (2.7 63.3 60.4-CH3C6H4CH3 (1.9 56.4.8 70.1 e .3 49.93 mmol).8 61.29 g.4-Cl2-C6H3CH3e a 60 67. a 3rd order polynomial was fitted to those intermediates of interest and the selectivity to aldehyde calculated from the polynomial equations as a function of substrate conversion.59 20 18 16 14 Relative Amount (mmoles) 12 10 8 6 4 2 0 0 10 20 30 Tim e (M inutes) 40 50 60 Me-Ar -Me Me-Ar-CHO Me-Ar-COOH OHC-Ar-COOH HOOC-Ar-COOH Figure 3. 26.37 mmol).95 g.0 72. 18. - MeOC6H4CH3 (2. These results were used to determine the selectivity to aldehyde at specific substrate conversions as illustrated in Table 3. Table 3.27 g. 17.1.05 mmol). .

give higher aldehyde selectivities than toluene.1 show that the benzaldehyde selectivity decrease as the substrate conversion increases. which means that processes aimed at producing the aldehyde specifically will need to be run to limited substrate conversions (probably in the order of 20%).2. higher aldehyde selectivities will only be feasible at lower substrate conversions. These results show exactly the same trend as observed above for aldehyde selectivities. . however. It should. containing electron withdrawing groups.60 The results in Table 3. while 4-chlorotoluene and 2. give lower aldehyde selectivities.4-Cl2-C6H3CH3 Amount (%) 26.2 Maximum amounts of aldehyde formed Substrate C6H5CH3 4-CH3C6H4CH3 4-MeOC6H4CH3 4-ClC6H4CH3 2.3 34.3 15. which contain electron donating groups on the aromatic ring.4dichlorotoluene. Thus.1 It would not be unreasonable to expect 3-alkyl-4-methoxytoluenes to behave similarly to 4-methoxytoluene and other substrates containing electron donating groups on the aromatic ring to give somewhat higher aldehyde selectivities. A comparison of the maximum aldehyde “yields” (determined at the point on the respective aldehyde curve where δ (aldehyde) = 0 ) for the above δ (time) reactions are shown in Table 3. Thus.1 show that the aldehyde selectivity increases with increasing electron density on the aromatic ring. or at least of the same order of magnitude as 4-methoxytoluene.2 24. Table 3.4 36. both p-xylene and 4methoxytoluene. also be noted that the results in Table 3.

which result in the formation of more energetic radicals (e. the “Rate” indicated in Table 3. several oxidation reactions were performed at different reaction temperatures.72 mmol) in a 1:1 molar ratio as the catalyst. This increase in rate is directly the result of the increase in the rate of initially formed peroxy (RCH2OO•) or hydroperoxy (HOO•) radicals as the reaction temperature is increased. This region was selected for measuring this rate so as to minimise interference of other reactions (e.3 show that as the reaction temperature is increased. 4methoxytoluene (2. Before commenting on the results obtained. alkoxy radicals – RCH2O•) which increase the rate of hydrogen abstraction from substrate molecules.61 3. and dioxygen as the oxidation gas at a flow rate of 30 mL min-1. Table 3. . further oxidation of intermediates such as benzylic alcohols and aldehydes) on the rate of substrate conversion. catalytic air oxidation reactions can be expected to be influenced significantly by the reaction temperature at which oxidations are performed.93 mmol) and NH4Br (0.85 mmol). However.5 mL) of the reaction mixture were withdrawn at regular intervals and analysed by gas chromatography. the initial rate of substrate conversion increases substantially. In order to investigate the effect of reaction temperature on the oxidation of 4-methoxytoluene and the selectivity to 4-methoxybenzaldehyde.3 refers to the rate of substrate consumption in the region 0 – 10 % of substrate conversion as measured by the slope of the substrate disappearance curve. the selectivity to aldehyde decreases. 18.g. The results depicted in Table 3.48 g. various reaction temperatures between 55 oC and 105 oC. These oxidations were carried out using cobalt(II) acetate (0. as the temperature and reaction rate increases. Aliquots (0.3 Catalytic air oxidation: Reaction temperature Being a free-radical reaction.g.1. 1.3 summarises the results obtained.168 g. glacial acetic acid (50 mL) as the reaction solvent. 1.30 g.

3 Effect of Reaction Temperature on Oxidation Rate and Aldehyde Selectivity Rate (mol dm-3 min-1) -0.85 x 10-2 -1.82 x 10-2 -1.5 83.5 60 Temperature ( C) 55 65 75 85 95 105 o The optimum oxidation temperature (defined as the temperature at which the high aldehyde selectivities are achieved at acceptable rates of oxidation) will therefore be a compromise situation and is probably in the region of 85 – 90oC.2 74.2 70.6 56. This process destroys the initially active Co(II)-Br catalyst species and which is not readily converted back into an active form.3 71.62 Table 3. been shown64 that bromide is converted into an inactive form.5 65.8 61.0 66. the active catalyst during the cobalt(II) acetate bromide catalyzed air oxidations of alkylbenzenes are thought to be a complex containing a direct Co(II) – bromide bond.3 72. and therefore aldehyde selectivity will decrease as a result of the conversion of the active catalyst species into a non-bromide containing form.8 67.33 x 10-2 -1.4 79.8 74.47 x10-2 -0. It has.0 68. in particular benzylic bromides.81 x 10-2 Conversion (%) 20 40 Selectivity (%) 83.8 75.1 58.4 Catalytic air oxidation: Effect of catalyst concentration As discussed earlier. several reactions were .77 x 10-2 -1.1 79. In order to determine whether the use of a higher amount of catalyst concentration (while keeping the Co:Br ratio constant at 1:1) will improve aldehyde selectivity during these oxidation reactions.65 It has also been shown66 that aldehyde oxidation starts to dominate once the bulk of “inorganic” bromide has been converted into “organic” bromide.1. 3.3 52. however.

8 72.02 M.4 79. The observed increase in selectivity is.1 49. however.1 M during the Co-Brcatalysed air oxidation of 4-methoxytoluene.3 67.01 M – 0. a reaction temperature of 95 oC and dioxygen as the oxidation gas at a flow rate of 30 mL min-1.1 69. glacial acetic acid (50 mL) as the reaction solvent.9 78.0 67. This effect is especially noticeable at lower conversion levels.10 38.4 summarises the results obtained. Table 3.7 49. Aliquots (0.63 carried out in which 4-methoxytoluene (2.01 0.6 52.06 0.9 60 32.04 0.85 mmol) was oxidised using various concentrations of cobalt(II)acetate and NH4Br in a 1:1 molar ratio as the catalyst.30 g.8 The results clearly show an increase in 4-methoxybenzaldehyde selectivity as the catalyst concentration is increased from 0.5 mL) of the reaction mixture were withdrawn at regular intervals and analysed by gas chromatography.4: Initial catalyst concentration Conversion (%) [ Co ] (mol dm ) 0. probably not significant enough to warrant the large increase in catalyst . but at higher conversion levels there is virtually no effect on the selectivity to 4-methoxybenzaldehyde once the cobalt concentration is raised above 0.7 82.02 0. Table 3. 18. concentration.8 63.5 -3 20 40 Aldehyde Selectivity (%) 35.8 54.

2 54. the reaction selectivity decreases significantly. 67 Coulometric analysis of the glacial acetic acid used during this investigation yielded an average value of 0.0 79. In previous studies into the effect of water concentration of the rate of substrate oxidation during the cobalt-bromide catalysed air oxidation of alkylbenzenes. increasing amounts of deionized water was added to a known mass of glacial acetic acid.5 Catalytic air oxidation: Effect of water concentration Water is continuously formed during the catalytic air oxidation of organic compounds and since the cobalt-bromide catalyst used during these oxidation reactions are susceptible to hydrolysis.1 2. For the purpose of this investigation on the effect of water in the glacial acetic acid used as the reaction solvent during the oxidation of 4-methoxytoluene.3 76.1% water.5. it . Thereafter.9 59. it was important to investigate the effect of increasing water levels in the oxidation mixtures.3 54.7 62.7 66.4 66.5%.8 66.2 20 40 Selectivity (%) 69.0933% (m/m).1 58.8 70.9 52.64 3.0 6. The results obtained are depicted in Table 3.0 8.0 4.1 60 The results obtained show an interesting trend (also observed with other substrates previously for rate enhancement)65 in that the selectivity to 4methoxybenzaldehyde improves as the water concentration is increased from 0.1.4 51. Glacial acetic acid has been reported to contain about 0.5: Effect of water concentration Conversion (%) [H2O] (mass %) 0. Table 3.9 87.2% to about 2.

5%).5%. and decreased aldehyde selectivities are observed. for example a 4-methoxy-2-alkylbenzaldehyde by means of a cobalt(II)acetatebromide catalyzed air oxidation process.2 Indirect oxidation of 3-tert-butyl-4-methoxytoluene 3. recycled.1. the extent of cobalt(II)-bromide coordination (as shown by UVvisible studies) increases.1 Introduction Oxidation and reduction processes in organic synthesis can be carried out effectively with traditional stoichiometric redox reagents.2. in glacial acetic acid the cobalt(II) – bromide interaction is somewhat suppressed.5%. the cobalt(II)bromide interaction decreases. The substrate conversion is restricted to <30%. and where feasible. While therefore not practically impossible to devise a process for producing. and the large amounts of solvent and oxidation products that will need to be separated. discussed in some detail in the preceding sections. mainly as a result of hydrolysis.65 was shown that the observed increase in catalyst performance as the water concentration is increased to about 2. etc. Above water concentrations of 2. Although there are . but as the water concentration is increased (to about 2. is directly related to the ability of cobalt to coordinate bromide. water content of the reaction mixture. such a process will not be cheap or technically easy in view of the challenge to effect proper mass transfer at larger scales. 3. 3.6 Catalytic Air Oxidations: Concluding Remarks The results on the catalytic air oxidation of various substituted alkyl aromatics.68 a large number of which are amenable to electrochemical regeneration. are carefully controlled. and Other reaction variables that include reaction temperature. suggest that high aldehyde selectivities (>70%) will only be achieved if: • • • The substrate contains electron donating groups on the aromatic ring. Thus.

" A high solubility in the aqueous supporting electrolyte is desirable to maximize the reaction rate with the organic species. most suitable redox couples are inorganic reagents and examples of those which are commonly used are: For oxidation: For reductions: Ce3+ / Ce4+. including: " The oxidized and reduced forms of the mediator must be chemically stable and not undergo side reactions which are irreversible. Cl-/ClO-.69 . some even to full scale manufacturing plant especially in the fine chemical and pharmaceutical industries. Na+/NaHg An advantage of using stoichiometric oxidation/reducing agents is the possible regeneration of these agents by electrochemical oxidation or reduction. reduction in any problems of effluent treatment and eliminate the need for bulk storage of hazardous or toxic chemicals on the site. " The electron transfer with the electrode should ideally be fast and reversible. Ni(OH) 2/NiOOH Sn4+/Sn 2+ . Mn2+/Mn3+. " Redox reactions with species other than the target molecule should be minimal. which leads to simplification in the process operation. Cr3+/Cr2O2-7.66 exceptions. " The cycle time for recovery or regeneration of the mediator should be high. this reduces cell voltage and the possibility of undesirable side reactions. There are several requirements for successful electrochemical mediators. Zn2+/Zn. Ce3+/Ce2+. Many of these processes have been tested and developed to the pilot plant level. Ti4+/Ti3+. Br-/ Br2. Mn2+/MnO2.

t-BMT Reactor Ce3+ t-BMB Oil / Water Separator Ce3+ Ce4+ Electrolysis Ce3+ Ce4+ Scheme 3.3 shows the reactions involved in the CeIV methanesulfonate mediated oxidation of the 3-tert-butyl-4-methoxytoluene to the corresponding benzaldehyde.70 An example of such a process is shown in Scheme 3.2: Ex-cell method for indirect electrochemical oxidations Scheme 3. This is then followed by a second two electron oxidation step from the alcohol to the benzaldehyde.67 Indirect electrochemical reactions are classified into two categories: In cell or Excell processes. . The first step involves a two electron oxidation of the methyl group of the toluene to the alcohol with a concurrent reduction of CeIV to CeIII. In the ex-cell process the reaction between a mediator and the substrate occurs in a chemical reactor separate from the electrochemical cell.2.

the mediator and the reactant are placed in one electrochemical cell unit. The spent mediator is re-oxidized in situ and the cycle is repeated. .3 Reaction sequence for the Ce(IV) oxidation of 3-tert-butyl-4methoxytoluene. After the reaction is completed. This then generates the mediator at the surface of the electrode material which then oxidizes the substrate.68 H3C H3C O H3C CH3 CH3 O H3C CH3 CH3 + 2 CeIV + O H H + 2 CeIII + 2H+ CH3 H3C O H3C CH3 CH3 OH H3C O H3C CH3 CH3 + 2 CeIV + 2 CeIII + 2H+ H O O Scheme 3. however. which can result in electrode fouling and deactivation. With the In-cell process. the mediator is separated from the organic products and returned to the electrochemical cell for regeneration. This is normally done in order to minimize contact of organic phase with the electrode surface.

70 . These factors introduce mass transfer limitations to the electro-synthesis procedure. The low amount of organic species in the electrolyte also limits the ability of the reactor to rapidly replenish the material consumed by the reaction in the aqueous phase.2.m-2 is to be achieved.m-3 if a practical current density of ca 100A. In terms of the mass transfer requirements at electrodes.70 Substrate Indirect electroreactions Product Electron Carrier active for oxidation Electron Carrier active for reduction Electrodes Scheme 3.69 The regeneration is normally carried out on a continuous basis for as long as the reaction proceeds.4: Recycling of the mediator in the electrochemical cell 3. Limitations in Solubility during Organic Electrochemical Processing The commercial development of electro-organic synthesis in aqueous electrolyte media is frequently limited by low concentrations of organic reagent in the electrolyte and thus by a low value of diffusion limiting current density. calculations put limits of organic depolariser concentration at ~100 mol.2.

72 The first mediator tested for the indirect electrochemical oxidation of 3-tert-butyl4-methoxytoluene was ceric amminium nitrate.5: Constant conditions: Ceric ammonium nitrate method Variable Methanol Stirring rate (rpm) Temperature (oC) Substrate: Ce(IV) ratio* Time Value 50 mL 400 30 1: 4 30 min * (NH4)2Ce(NO3)6 (8. the relevant amount (Table 3. The results of these experiments are summarised in Table 3. . the precipitated cerium salts were recovered and the cerium(III) oxidised to cerium(IV) as described in section 2.3 Ceric Ammonium Nitrate71.337 mmol).7. 3-tert-butyl-4-methoxytoluene (0. 16.5 lists the experimental conditions that were kept constant throughout this investigation.70 3.7. Table 3.1).9567 g.6509g.7. After work-up (section 2.656 mmol). Table 3. The oxidation reactions with ceric ammonium nitrate were carried out as described previously in Section 2.1 After determining the actual concentration of cerium(IV) in the re-oxidised solutions.2.2. 3. This procedure was repeated twice.2.6) of 3-t-butyl-4-methoxytoluene was added and the solution oxidised as before.2.6 below.

Ce(IV) (mmoles) 16. methoxybenzaldehyde From Table 3.4.3. which were determined by titration against ferrous ammonium nitrate.98 11. 3.01 9. prepared as described previously in Section 2.496 2.89 = 3-tert-butyl-4tert-BMB** (%) 3-tert-butyl-4-methoxytoluene. The first step on this section was to decide on the concentration of methane sulfonic acid to use in order to prepare a Ce(IV) methanesulfonate. .42 76. What is important to note. varies between about 10 mmoles and 16 mmoles.4 Indirect electrochemical oxidation of 3-tert-butyl-4-methoxytoluene using Cerium(IV) Methanesulfonate The next mediator system evaluated for the indirect electrochemical oxidation of 3-tert-butyl-4-methoxytoluene was cerium(IV) methanesulfonate.779 tert-BMB 73.18 80.7 below were evaluated and a decision was taken based on the results.6 Cycle No.2. is the observation that the amount of 3-tert-butyl-4-methoxybenzaldehyde formed during these oxidation reactions remain fairly constant (probably within experimental error) around the 75% mark during the 3 cycles.6 it can be seen that the amount of Cerium(IV). Different concentration levels as shown in the table 3.2.71 Table 3. however. This variation is probably the result of variations in the re-oxidation efficiency of the Cerium(III).11 = tert-BMT* (mmoles) 4. 1 2 3 * tert-BMT Indirect electrochemical oxidation of 3-tert-butyl-4- methoxytoluene using ceric ammonium nitrate.003 2.

namely acetone.72 Table 3.0369 3-tert-butyl-4-methoxytoluene. 6M concentration was chosen as the better range of methane sulfonic acid concentration. These reactions were performed as described in Section 2. to attempt improving the mass transfer between the two reaction phases.2889 t-BMB** Selectivity % 32. Cerium(IV) methanesufonate concentration 8M 6M 4M 2M * tert-BMT = t-BMT* Conversion % 15.1832 73. probably as a result of the poor mass transfer between the two immiscible phases.4.6 illustrate the effect of poor mass transfer even in reactions where a co-solvent such as acetone is used.0156 0.8253 51.2. .7093 17. acetonitrile and dichloromethane. The results depicted in Table 3. Initial reactions were carried out by directly with contacting aqueous the organic phase phase (3-tert-butyl-4(cerium (IV) methoxytoluene) the oxidation methanesulfonate typically in 6M methane sulfonic acid). These reactions gave rather disappointing results (typically 35 – 40% over a 6 hour reaction period).7) trial reactions.9361 t-BMB** Yield % 5.9402 2.4 and where the 3-tert-butyl-4methoxytoluene was dissolved in 10 mL of acetone.03558 24.0369 100 tert-BMB 0.7: Effect of Methane sulfonic acid concentration on the oxidation of 3-tert-butyl-4-methoxytoluene using Cerium(IV) Methanesulfonate. For this reason it was decided to rather perform these oxidations in the presence of co-solvents. = 3-tert-butyl-4- methoxybenzaldehyde After the summarized (Table 3.1543 3.

several reactions were carried out at various reaction temperatures as described in section 2.044 mmoles TBMT = 0.3 molar) together with 10 mL of each solvent.-butyl-methoxybenzaldehyde From the results depicted in Table 3.511 mmoles 41.8 Effect of stirring rate on the cerium(IV) methanesulfonate mediated oxidation of 3-tert-butyl-4-methoxytoluene in the presence of acetone as co-solvent.00 100. In order to evaluate the effect of the selected solvent systems on the cerium(IV) methane sulfonate-mediated oxidation of 3-tert-butyl-4-methoxytoluene.49 mmoles TBMT = 0. 1350 rpm TBMT* Conversion (%) TBMB** Selectivity (%) TBMT* Conversion (%) TBMB** Selectivity (%) a– 1500 rpm Run 1 Cea = 2. All further investigations were carried out at the higher stirring rate of 1500 rpm.622 mmoles 54.00 100.2.6 it can be seen that the rate of mixing significantly influences the degree of conversion of substrate.61 71.00 Cerium (IV) methanesulfonate.-butyl-methoxytoluene **TBMB = Tert.25 65.4 and using cerium(IV) methane sulfonate (11.37 100. Methanesulfonic acid [6M]. at 21 oC * TBMT = Tert. 75 mmol) relative to the amount of cerium (IV) methane sulfonate .0 mmoles) in an aqueous methane sulfonate solution (6.73 Table 3. hence reaction rate.18 100.4.00 Run 2 Cea = 2. but has no influence on the reaction selectivity. The amount of substrate (3-tert-butyl-4-methoxytouluene) was kept constant (~2.

15 86.2 illustrates a typical GCMS-chromatogram obtained for the oxidation of 3-tert-butyl-4-methoxytoluene (retention time = 8.9 Oxidation of 3-tert-butyl-4-methoxytoluene with cerium(IV) TBMT Conversion (%) methane sulfonate in the presence of various solvents. .21 83.01 92.37 min). Solvent Temperature (oC) TBMB Yield (%) 21 Acetone 30 Reflux 95.21 66.21 93.13 40 50 Acetonitrile 60 70 Reflux 98.7 it can be seen that the oxidations in the presence of acetone and dichloromethane are quite selective.74 (1 : 4).90 From the results depicted in Table 3. The results obtained for these investigations are summarised in Table 3.7.98 58.45 99. Table 3.80 55.95 Dichloromethane 30 Reflux 87. Figure 3.51 97.72 53.05 95.13 87. resulting in the production of the 3-tert-butyl-4-methoxybenzaldehyde in near quantitative selectivity.25 61.54 min) in the presence of acetone and which only shows peaks for the starting material and product 3-tert-butyl-4-methoxybenzaldehyde (retention time = 12.98 41.21 93.21 83.60 81.

39 4 6 8.34 17.3) for the oxidation of t-butyl methoxytoluene at 60 oC.02 2.54 9.52 14 16 12.13 minutes) readily occurs as the oxidation temperature is increased above 50 oC as shown in the GCMS-trace (Figure 3.02 8 10 Time (min) 11.56 14.10 2 4.17. however.37 NL: 2.97 100 95 90 85 80 75 70 65 Relative Abundance 60 55 50 45 40 35 30 25 20 15 10 5 0 1.75 RT: 0. In acetonitrile.18 8.25E8 TIC MS ACETONE3 0 Figure 3. over oxidation of the initially formed benzaldehyde to the 3-tert-butyl-4-methoxybenzoic acid (retention time = 14.28 16.2 Typical GCMS-trace for oxidations in the presence of acetone.16 . .27 5.98 12 12.

86 16. however. cerium(IV) methane sulfonate is capable of giving the desired product in near quantitative selectivity at substrate conversions as high as 90%. and in the case of acetonitrile.34E7 TIC MS Rxn200606-26-03 10.24 4.18.01 100 95 90 85 80 75 70 65 Relative Abundance 60 55 50 45 40 35 30 25 20 15 10 5 0 2 4 6 8 10 Time (min) 12 14 16 18 1. results in the further oxidation of the desired aldehyde . results in slow mass transfer in these oxidations.5 Indirect Electrochemical Oxidations: Concluding Remarks Oxidations carried out using the inorganic mediators ceric ammonium nitrate and cerium(IV) methane sulfonate has shown that these methods are capable of producing significantly improved results compared to catalytic air oxidations. The low solubility of the substrate in the aqueous methane sulfonic acid solutions.03 8.76 12.05 3.41 9. 3.16 3.08 Figure 3.3 GCMS-trace for the oxidation of 3-tert-butyl-4-methoxytoluene in the presence of acetonitrile at 60 oC.60 8.00 2.39 6. The use of polar solvents as co-solvents alleviates this problem only slightly.12 NL: 2.13 12.24 . In particular.2.85 14.76 RT: 0.

2) In equations 3. Constant current electrolysis: Throughout the reaction.73. . As the reaction proceeds (i. While a reduction in the methanesulfonic acid concentration may reduce the oxidation strength of the cerium(IV).77 through to the benzoic acid.2 the symbols used have the following meaning: • Q is the number of coulombs consumed in an electrolysis.3 Direct Electrochemical Oxidations 3.e. the current in the cell gradually decreases.3. the current is kept constant whilst the potential of the electrolysis system changes gradually as the reaction proceeds. oxidisable material reduces). 74 Q = ∫ 0∞ Idt = nFN Q = ∫ 0∞ Idt = It = NFn (3. this will again reduce the rate of oxidation. 3.1 and 3. thereby reducing the extent of benzaldehyde oxidation.1 Constant current and constant potential electrolysis Electrochemical reactions are normally carried out using two of the following procedures: constant current or constant potential electrolysis.1) (3. the potential of the working electrode is kept constant with respect to a reference electrode. The following equations are used to determine the amount of charge passed through a reaction mixture during constant potential and constant current electrolysis respectively. 74 Constant potential electrolysis: As the name suggests.

which are mentioned below:73. i.73 3. n is the total number of electrons involved per molecule for the oxidation/reduction process. t is the time (seconds). F is the Faraday constant.75 Cell design: This is less complicated in an undivided process than it is in a divided process.3. The difference between the two is explained below:73. • N is the number of moles of substrate initially present. the two electrodes are immersed in one solution. and. i.2 Undivided vs Divided Both direct and indirect electrolysis procedures can be carried out using undivided (one compartment) or divided (two compartments) cells. The separator used in the divided cell can also cause problems: . formed at one electrode. Each of these cells has its own advantages and disadvantages in electrochemical synthesis.e. the charge needed (96500 coulombs) per mole of substrate to effect the electrochemical reaction. 75 Undivided: Here there is no separation between the anode and the cathode.73 Divided: Here there is a physical separation (micro-porous divider/membrane) between the anolyte and the catholyte. from migrating to the other where it can undergo additional redox reactions. The above processes have both advantages and disadvantages when compared to each other.e. This prevents products.78 • • • • I is the current (Ampere). assuming there is a one electron change.

3. the electrode surface and presence of the adsorbed species. facilitate the possibility of performing paired synthesis. which then further form intermediate species which themselves may undergo further electron transfer. Here is an ideal direct electro organic synthesis reaction. Reactions: A divided cell prevents the occurrence of side reactions. totally depends on the surrounding homogeneous electrolyte (which is the solvent) and other species. the mechanism by which the process occurs often start with the formation of radical ions. radical disproportionation and radical-radical dimerisation. it is known that a undivided reactor is cheaper than a divided reactor by and order of magnitude.3 Mechanistic considerations Even though there is a huge range and wide diversity of organic electrosynthesis processes. the chemical reactivity of the radical ion is purely determined by the ionic character of the species and by the radical itself.3) The final destination of the unstable ion radical.79 the cell resistance is increased and this problem could be magnified if fouling of the separator occurs.ion ) − Fast Intermediate + e − → Pr oduct →  (3. The divided cell does. When considering scaling-up. On the other hand. however.. which can occur at a counter electrode. that is the type of product formed. Organic + e → ( rad. radical addition. if any.76 3. The electron transfer process adds further control parameters in providing possible selective synthesis. where two distinctly separate reactions could be carried out in the same reactor at the same time. which can undergo typical radical reactions such as hydrogen abstraction. .

Naturally. The reaction paths for radical anions obtained from unsaturated hydrocarbons. adding to available nucleophiles.80 Radical cation. Radical cations may also add to unsaturated hydrocarbon molecules or can react further to give alkyl radicals. Anionic reaction radical anions may be protonated to form radicals and undergo Michael additions of the radical anions. optimizing the reaction conditions and designing suitable process electrolysis cells requires. the process of mechanism elucidation is also indispensable for the generation of new research ideas. can also be expected to have the properties of electrophiles. include hydrogen abstractions.77 In this section factors which could influence or have an impact on the mechanism of the direct electrochemical oxidation of substituted toluenes to the corresponding benzaldehydes will be considered. e. for example. This is due to the fact that proton donors cannot be completely eliminated from electrolytes. . vinyl compounds. catalytic hydrogenation. due to the positive charge. This often leads to undesirable electro-polymerisation.g. The radical cation reactions are more important than the radical anion reactions. elucidation of the reaction mechanism and optimising the experimental conditions in electrochemical reactions is not as complicated as in other heterogeneous reactions. at least. Theoretically. except in the case of protonation to form the respective radical. radical reactions with the electrode material. radical anion disproportionation and radical dimerisation. a good working knowledge of the reaction mechanism. in order to facilitate the optimization of the selected oxidation reaction. The selection of a suitable supporting electrolyte and solvent type for a particular electrolytic oxidation. which is routinely used in organic synthesis.

The nature of the anion present in the supporting electrolyte greatly affects the yield of the α-methoxylated product. which strongly suggests that an indirect mechanism operates in the α-methoxylation of alkyl aromatics such as toluene. 81 Both nuclear and side-chain methoxylation have been performed on aromatic compounds.82 F.≈ CH3O. HX + . alkenes and ethers. sodium salt (BSANa)78. and NaClO4.81 3.3.≈ OH. KF79. ArCH2 + + e - X = HOCH2 or CH3O ArCH2OCH3 + CH3O or ArCH2 + + CH3OH ArCH2OCH3 + H + . Methanolic electrolytes have been shown to undergo oxidation at lower potentials than many organic substrates.> CN. Substrates that have been alkoxylated in this manner include aromatic compounds.> Cl. the effectiveness decreasing in the series. H2SO4. + + H + + e - or CH3O ArCH3 - CH3O e - +X ArCH2 .≈ ClO4. ArCH2 .80.3 Electrochemical alkoxylation Alkoxylation can be achieved by the anodic oxidation of the substrate in an alcohol medium such as methanol containing a suitable supporting electrolyte such benzensulfonic acid.> BrThe mechanism for the anodic methoxylation of alkyltoluenes is illustrated below: CH3OH HOCH2 .

The electrochemical oxidation of toluenes in dry methanol leads to methoxylation of the side-chain when non nucleophilic electrolytes were used. . side chain methoxylation to produce the intermediate 3-tert-butyl-4-methoxy benzyl methyl ether.83 In alkaline medium. as shown in Scheme 3. is expected.to be oxidized at all under these conditions. The radical HOCH2• is the most likely candidate since the O-H bond in MeOH is much stronger than the C – H bond.82 One would not expect F.is probably the electroactive species.4: Side chain methoxylation of 3-tert-butyl-4- methoxytoluene to produce the 3-tert-butyl-4-methoxy benzyl methyl ether. using non-nucleophilic supporting electrolytes such as benzene sulfonic acid.4. sodium perchlorate.or ClO4. MeO. O CH3 CH3 CH3 CH3 -e+ O C CH3 CH3 CH3 CH3 O C + CH3 CH3 CH3 CH3 O CH3 CH3 CH3 CH3 -H+ C CH3 O CH3 CH3 CH3 CH3 CH3 CH3 CH3 O CH3 CH3 CH3 CH3 O CH3 CH3 CH3 CH2 -e- MeOH -H+ CH2 CH2 + O CH3 Scheme 3. potassium fluoride and sulfuric acid. which suggest that methanol is the likely electroactive species. and MeO• would then be X.84 Since side chain methoxylation during this investigation was investigated in dry methanol. forming a radical intermediate that then functions as X in the above equations.

This step should be easier than the first since the intermediate ether has a lower oxidation potential than the substrate. This follows an ECE (electrochemical chemical electrochemical) type reaction. O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 O O -2e-H+ O CH3 HC + MeOH -H+ CH3 CH3 CH3 O CH3 O CH3 O CH3 Scheme 3. it should be possible to accumulate the 3-tert-butyl-4methoxybenzaldehyde dimethyl acetal and minimizes further oxidation to the corresponding benzoic acid.83 Further electrolysis should repeat the sequence of reactions to form 3-tert-butyl4-methoxybenzaldehyde dimethyl acetal.11).5 Formation of 4-methoxybenzaldehyde dimethyl acetal By controlling the potential of the oxidation system accurately at the cell potential values indicated by the cyclic voltammogram of 3-tert-butyl-4-methoxytoluene (Figure 3. .

00E-03 CH3 O O CH3 1. .00E+00 0 500 1000 Potential (mV) 1500 2000 Figure 3.50E-03 2F O CH3 CH3 2F H3C CH3 2.50E-03 Current mA 1.11 Cyclic voltammogram of the 3-tert-butyl-4-methoxytoluene on a graphite surface in a 0.84 CH3 H3C CH3 CH 3 O H3C O H3C O CH3 CH3 CH3 H3C 2. which is then further oxidized to the 3-tert-butyl-4-methoxybenzaldehyde dimethyl acetal at about 1653 mV.5 M NaClO4 / acetonitrile medium. Figure 3.12 shows the cyclic voltammogram for 3-tert-butyl-4-methoxybenzaldehyde dimethyl acetal on graphite electrodes in a acetonitrile / sodium perchlorate medium. The cyclic voltammogram shows the anodic oxidation cycle for 3-tert-butyl toluene to produce the 3-tert-butyl-4-methoxybenzyl methyl ether at about 1193 mV.00E-04 0.00E-03 5.

certain criteria have to be met.00E-04 0.00E-04 Current mA 6.5 M NaClO4 / acetonitrile medium. It could also be seen that there is a second oxidation peak at 2200 mV which is quasi reversible.3.85 1. and Low cost. From the cyclic voltammogram it can be seen that the 3-tert-butyl-4methoxybenzaldehyde dimethyl acetal is oxidized at about 152O mV indicating that for the direct synthesis to be selective.00E-03 8.00E-04 2. 3. the anodic oxidation must be performed at a slightly lower oxidation potential.4 Supporting Electrolyte Investigations When selecting a suitable electrolyte.12 Cyclic voltammogram of 3-tert-butyl-4-methoxybenzaldehyde dimethyl acetal on a graphite surface in a 0. Electrochemical stability.00E+00 0 -2.00E-04 Potential (mV) 500 1000 1500 2000 2500 3000 Figure 3. Ease of preparation.00E-04 4. These are: • • • • • Good solubility in the solvent to be used. No reactivity towards the reaction intermediates.85 .

Two sets of experiments were conducted with each electrolyte. and they were as follows: benzenesulfonic acid. not only to provide a means of carrying the electrolysis current. 3.1 Conductivity Studies of the Supporting Electrolytes Figure 3. followed by NaClO4.4.86 A supporting electrolyte is nearly always necessary during the electrolysis of an organic species. potassium fluoride (KF).84 Several supporting electrolytes were chosen for this part of the investigation. firstly to evaluate the conductivity of the electrolyte in methanol as a function of its concentration. but also to reduce the rather large electrical resistance encountered in organic solvents.3. The electrolytes can be arranged in the following order according to their conductivity: H2SO4 > NaClO4 > BSANa > KF .13 shows a plot of conductivity (mS cm-1) against concentration units for each supporting electrolyte in methanol at 22oC. and sulphuric acid (H2SO4). sodium salt (BSANa) sodium perchlorate (NaClO4). and secondly to study the electrochemical stability of the electrolyte. H2SO4 shows the highest conductivity.

15 0.45 0.1 mol dm -3).87 30 Cond (mS cm-1) 25 20 15 10 5 0 0.05 mol dm -3) in acetonitrile medium.2E-17 1E-17 Current (mA) 8E-18 Trillions 6E-18 4E-18 2E-18 0 -2E-18 0 100 200 300 Pot (mV) NaClO4 H2SO4 KF BSANa 400 500 600 Figure 3.2 0.14 shows the polarization curve for each supporting electrolyte at a constant concentration of 0.25 0. 1.4. using graphite as working electrode versus Ag / Ag+ (0.3 Conc (M) KF NaClO4 BSANa H2SO4 0.14: Polarisation curves for different supporting electrolytes (0.3. 3.35 0.5 M in methanol.5 Figure 3.4E-17 1. .13 Conductivity studies for different supporting electrolytes using Pt as electrode in a methanol medium.4 0. obtained from a linear sweep.2 Stability Studies Figure 3.1 0.

These reactions were carried out using a stainless steel electrode for the cathode material and a graphite electrode for the anode material.5 A.5.15 to 3. when using BSANa as the supporting electrolyte.5 M supporting electrolyte at a current of 1. Samples of (ca.00 mL methanol containing 0.5 g. 30.3. 40.15 to 3. 3.014 moles) in 150. 50 and 60 oC.3 mL) were taken every 30 minutes and analysed by gas chromatography as described previously (section 2. .1 Benzenesulfonic acid. sodium salt Product distribution diagrams of the direct electrochemical oxidation of t-butyl methoxytoluene at four electrolysis temperatures.88 From the above it can be seen that.18.5 Product distribution diagrams Several reactions were carried out to investigate the effect of the different supporting electrolytes on the direct electrochemical oxidation of 3-tert-butyl-4methoxytoluene in methanol. 0. are illustrated in Figures 3.1).3. 0. The results obtained are summarised graphically in Figures 3. with NaClO4 showing the lowest current by-pass indicating that it can be the most stable supporting electrolyte.21. using the following conditions: 3-Tert-butyl-4methoxytoluene (2. These reactions were carried out at four different reaction temperatures. for the linear sweep of all the electrolytes show good electrochemical stability in acetonitrile.3. 3.

89 100 90 Rel % Area mole 80 70 60 50 40 30 20 10 0 0 30 60 90 120 150 180 Time (min) TBMT TBMBME TBMBDMA Sum Figure 3.20 Shows the effect of the supporting electrolyte benzenesulfonate.19 Shows the effect of the supporting electrolyte sodium benzene sulfonate at 30 oC 100 80 Rel % Area mole 60 40 20 0 0 30 60 90 120 150 180 Tim e (m in) TBM T TBM BM E TBM BDM A Sum TBM A Figure 3. sodium salt at 40 oC .

sodium salt 60 oC.90 100 Rel % Area mole 80 60 40 20 0 0 30 60 90 120 150 180 Time (min) TBMT TBMBE TBMBDMA TBMBA Sum Figure 3. sodium salt at 50 oC 100 Rel % Area mole 80 60 40 20 0 0 50 100 150 200 Time (min) TBMT TBMBME TBMBDMA TBMA Sum Figure 3.22 Shows the effect of the supporting electrolyte benzenesulfonate.21 Shows the effect of the supporting electrolyte benzenesulfonate. .

The substrate 3-tert-butyl-4-methoxytoluene decreased sharply to 20 % and then more slowly to 0 %. It was also observed that some acetal 3-tert-butyl-4-methoxybenzaldehyde dimethyl acetal hydrolysed to form the 3-tert-butyl-4methoxybenzaldehyde (4 %). The product 3-tert-butyl-4-methoxybenzaldehyde dimethyl acetal reaches a maximum of 66% at 150 minutes (3. b) At 40 oC the intermediate 3-tert-butyl-4-methoxy benzyl methyl ether reaches a maximum of 46 % at 90 minutes (2 F) and then decrease to 11 % at 180 minutes (4 F). while the easier oxidizeable species such as 3-tert-butyl-4-methoxy benzyl methyl ether is oxidized. The sum slightly decreases after 150 min to about 95 %.3 F).91 The following observations can be made: a) At 30 oC the intermediate 3-tert-butyl-4-methoxy benzyl methyl ether reaches a maximum of 18 % after 90 minutes ( or 2 Faradays of charge) and then continues to drag out over the duration of the time. whilst the easier oxidizeable species such as 3-tert-butyl-4-methoxy benzyl methyl ether is oxidized. The product 3-tert-butyl-4-methoxybenzaldehyde dimethyl acetal reaches a maximum of 84 % at 180 minutes (4 F). . c) At 50 oC the intermediate 3-tert-butyl-4-methoxy benzyl methyl ether reaches a maximum of 46 % at 90 minutes (2 F) and then decrease to 19 % at 180 minutes (4 F). It was also observed that some acetal 3-tert-butyl-4-methoxybenzaldehyde dimethyl acetal hydrolysed to the 3-tert-butyl-4-methoxybenzaldehyde (2 %). the sum also decreases after 120 min to about 85 %. The product 3-tert-butyl-4-methoxybenzaldehyde dimethyl acetal reaches a maximum of 78 % at 180 minutes (4 F). The substrate 3-tert-butyl-4methoxytoluene gradually decreased to zero at 180 min (4 F). The substrate 3-tert-butyl-4-methoxytoluene decreased sharply to 6 % after 90 minutes and then slowly to 0 %.

40.92 d) At 60 oC the intermediate 3-tert-butyl-4-methoxy benzyl methyl ether reaches a maximum of 76 % at 120 minutes (3 F) and then decrease to 33 % at 180 minutes (4 F). It was also observed an initial increase in 3-tert-butyl-4-methoxybenzaldehyde concentration. And the next oxidizable species was the ether 3-tert-butyl-4-methoxy benzyl methyl ether showing a fast anodic oxidation to the acetal 3-tertbutyl-4-methoxybenzaldehyde dimethyl acetal.23 Shows the effect of sulfuric acid as the supporting electrolyte at 30 oC . These reactions were carried out in the same manner as described for BSANa above.23 to 3.26. 100 80 Rel % Area mole 60 40 20 0 0 TBMT 30 TBMBME 60 Tim e (m in) TBMBDMA 90 TBMA 120 Sum Figure 3. 50 and 60 oC) is illustrated in Figures 3.3. 3. The product 3-tert-butyl-4-methoxybenzaldehyde dimethyl acetal stayed stable for the first 100 minutes at 30 % at this stage the substrate 3-tert-butyl-4-methoxytoluene been completely converted.5.2 Sulfuric acid The effect of sulfuric acid as supporting electrolyte on the direct electrochemical oxidation of 3-tert-butyl-4-methoxytoluene at the four reaction temperatures (30.

24 Shows the effect of sulfuric acid as the supporting electrolyte at 40 oC 100 80 Rel % Area mole 60 40 20 0 0 30 60 90 Tim e (m in) TBMT TBMBME TBMBDMA TBMA Sum 120 150 180 Figure 3.25 Shows the effect of sulfuric acid as the supporting electrolyte at 50 oC .93 100 Rel % Area Mole 80 60 40 20 0 0 30 60 90 Time (min) TBMT TBMBMR TBMBDMA TBMA Sum 120 150 180 Figure 3.

It was also observed that some acetal (3-tert-butyl-4-methoxybenzaldehyde . b) At 40 oC the intermediate 3-tert-butyl-4-methoxy benzyl methyl ether reaches a maximum of 44 % at 90 minutes (2 F) and then decrease to 15 % at 180 minutes (4 F). The substrate 3-tert-butyl-4-methoxytoluene gradually decreased to 8 % at 180 min (4 F). The product 3-tert-butyl-4methoxybenzaldehyde dimethyl acetal reaches a maximum of 78 % at 150 minutes (3. The product 3-tert-butyl-4-methoxybenzaldehyde dimethyl acetal reaches a maximum of 71 % at 180 minutes (4 F).5 F) and then continue to drag out over the duration of the time.26 Shows the effect of sulfuric acid as the supporting electrolyte at 60 oC. Trace amounts of 3-tert-butyl-4methoxybenzaldehyde (3 %) was observed.94 100 Rel % Area mole 80 60 40 20 0 0 30 60 90 120 150 180 Time (min) TBMT TBMBME TBMBDMA TBMA Sum Figure 3. The following observations could be made: a) At 30 oC the intermediate 3-tert-butyl-4-methoxy benzyl methyl ether reaches a maximum of 15 % at 60 minutes (1.3 F).

27 to 3. 40. d) At 60 oC the intermediate 3-tert-butyl-4-methoxy benzyl methyl ether reaches a maximum of 36 % at 90 minutes (2 F) and then stays constant for the remainder of the time.3.The sum slowly decreases after 120 min to about 80%. 50 and 60 oC) is illustrated in Figures 3. The substrate 3-tert-butyl-4-methoxytoluene decreased gradually to 0 %. These reactions were carried out in the same manner as described for BSANa above. It was also observed that some acetal hydrolysed to the 3-tert-butyl-4methoxybenzaldehyde (5 %). The substrate 3-tert-butyl-4-methoxytoluene decreased gradually to 2 %.5. 3.3 Sodium perchlorate The effect of sodium perchlorate as supporting electrolyte on the direct electrochemical oxidation of 3-tert-butyl-4-methoxytoluene at the four reaction temperatures (30. The product 3-tert-butyl-4-methoxybenzaldehyde dimethyl acetal reaches a maximum of 71 % at 150 minutes (4 F). . The sum slowly decreases after 120 min to about 80%.30. c) At 50 oC the intermediate 3-tert-butyl-4-methoxy benzyl methyl ether reaches a maximum of 36 % at 90 minutes (2 F) and then decrease to 21 % at 180 minutes (4 F). The product 3-tert-butyl-4methoxybenzaldehyde dimethyl acetal reaches a maximum of 69% at 150 minutes.95 dimethyl acetal) hydrolysed to the 3-tert-butyl-4-methoxybenzaldehyde (4 %). The substrate 3-tert-butyl-4-methoxytoluene decreased gradually to 0 %.

.26 Shows the effect of sodium perchlorate as the supporting electrolyte at 30 oC 100 80 60 40 20 0 0 30 60 90 120 150 Rel % Area mole Time (min) TBMT TBMBME TBMBDMA Sum Figure 3.27 Shows the effect of sodium perchlorate as the supporting electrolyte at 40 oC.96 100 Rel % Area mole 80 60 40 20 0 0 30 60 90 120 150 180 Time (min) TBMT TBMBE TBMBDMA TBMA Sum Figure 3.

28 Shows the effect of sodium perchlorate as the supporting electrolyte at 50 oC.29 Shows the effect of sodium perchlorate as the supporting electrolyte at 60 oC . 100 Rel % Area mole 80 60 40 20 0 -20 0 30 60 90 120 150 180 Time (min) TBMT TBMBE TBMDMA Sum Figure 3.97 100 Rel % Area mole 80 60 40 20 0 -20 0 30 60 90 120 150 180 Time (min) TBMT TBMBME TBMBDMA Sum Figure 3.

It was also observed that some acetal 3-tert-butyl-4methoxybenzaldehyde dimethyl acetal. The substrate 3-tert-butyl-4-methoxytoluene decreased gradually to 3 %. The substrate 3-tert-butyl-4-methoxytoluene decreased gradually to 3 %. . The substrate 3-tert-butyl-4methoxytoluene decreased gradually to 10 %. The product 3-tert-butyl-4-methoxybenzaldehyde dimethyl acetal reaches a maximum of 85% at 180 minutes. Trace amounts of 3-tert-butyl-4methoxybenzaldehyde (6%) was observed. c) At 50 oC the intermediate 3-tert-butyl-4-methoxy benzyl methyl ether reaches a maximum of 23 % at 90 minutes (2 F). d) At 60 oC the intermediate 3-tert-butyl-4-methoxy benzyl methyl ether reaches a maximum of 33 % at 90 minutes (2 F) and then decreased to 11 % at 180 minutes. b) At 40 oC the intermediate 3-tert-butyl-4-methoxy benzyl methyl ether reaches a maximum of 10 % at 90 minutes (2 F) and then stayed at 6 % till 180 minutes (4 F) passed. The substrate 3-tert-butyl-4-methoxytoluene gradually decreased to 2 % at 180 min (4 F). The product 3-tert-butyl-4methoxybenzaldehyde dimethyl acetal reaches a maximum of 93 % at 180 minutes (4 F).98 The following observations could be made: a) At 30 oC the intermediate 3-tert-butyl-4-methoxy benzyl methyl ether reaches a maximum of 15 % at 90 minutes (2 F) and then continues to drag out over the duration of the time. The product 3-tert-butyl4-methoxybenzaldehyde dimethyl acetal reaches a maximum of 85 % at 180 minutes (4 F). The sum accountability stays at 100 %. The sum accountability stays at 100 %. The sum accountability stays at 100 %. The sum accountability stays at 100 %. The product 3-tert-butyl-4methoxybenzaldehyde dimethyl acetal reaches a maximum of 80 % at 180 minutes (4 F).

50 and 60 oC) is illustrated in Figures 3.5.30 Shows the effect of potassium fluoride as the supporting electrolyte at 30 oC . 40. These reactions were carried out as described for BSANa above. Rel % Area mole 100 80 60 40 20 0 0 30 60 90 120 150 180 Time (min) TBMT TBMBME TBMBDMA TBMA Sum Figure 3.34.31 and 3.3.4 Potassium fluoride The effect of potassium fluoride as supporting electrolyte on the direct electrochemical oxidation of 3-tert-butyl-4-methoxytoluene at the four reaction temperatures (30.99 3.

100 Rel % Area mole 80 60 40 20 0 0 30 60 90 120 150 Tim e (m in) TBMT TBMBME TBMBDMA TBMA Sum Figure 3.32 Shows the effect of potassium fluoride as the supporting electrolyte at 50 oC. .100 100 Rel % Area mole 80 60 40 20 0 0 30 TBMT 60 TBMBME 90 Time (min) 120 150 Sum 180 TBMBDMA TBMA Figure 3.31 Shows the effect of potassium fluoride as the supporting electrolyte at 40 oC.

An amount of 11 % for the 3-tert-butyl-4-methoxybenzaldehyde was observed. The substrate 3-tert-butyl-4-methoxytoluene decrease rapidly to 90 min followed by a slow decrease to 5 % at 180 min (4 F).101 100 80 Rel % Area mole 60 40 20 0 -20 0 30 60 90 120 150 Time (min) TBMT TBMBME TBMBDMA TBMA Sum Figure 3.5 F) and then stayed at 14 % till 180 minutes (4 F) passed. The product 3-tert-butyl-4methoxybenzaldehyde dimethyl acetal reaches a 65 % at 90 minutes (2 F) and then continued to be formed with a maximum of 77% at 180 minutes. The following observations could be made: a) At 30 oC the intermediate 3-tert-butyl-4-methoxy benzyl methyl ether reaches a maximum of 13 % at 90 minutes (2 F) and then continues to drag out over the duration of the time. b) At 40 oC the intermediate 3-tert-butyl-4-methoxy benzyl methyl ether reaches a maximum of 13 % at 60 minutes (1. . The sum accountability stays at 100 %.3 F). The product 3-tert-butyl-4methoxybenzaldehyde dimethyl acetal reaches a maximum of 68 % at 120 minutes (3.33 Shows the effect of potassium fluoride as the supporting electrolyte at 60 oC.

At higher temperatures the acetal concentration reaches a maximum of only about 70%. c) At 50 oC the intermediate 3-tert-butyl-4-methoxy benzyl methyl ether reaches a maximum of 23 % at 70 minutes (1. The product 3-tert-butyl-4-methoxybenzaldehyde dimethyl acetal reaches a maximum of 65 % at 150 minutes. The product 3-tertbutyl-4-methoxybenzaldehyde dimethyl acetal reaches a maximum of 58 % at 120 minutes (4 F). An amount of 17 % for the 3-tert-butyl-4methoxybenzaldehyde was observed. d) At 60 oC the intermediate 3-tert-butyl-4-methoxy benzyl methyl ether reaches a maximum of 21 % at 90 minutes (2 F) and then decrease to 12 % at 180 minutes. At high temperature. The sum accountability stays at 100 %. The sum accountability stays at 100 %. sodium salt: At low temperatures the reaction is slow but results in a high yield of the desired acetal at 40 oC and 180 min.3. 3. The sum accountability stays at 100 %. the reaction is faster and the intermediate ether reaches a maximum of 80%. The substrate 3-tert-butyl-4-methoxytoluene decreased gradually to 2 %. .8 F).102 The substrate 3-tert-butyl-4-methoxytoluene decreased gradually to 2 %. • Sulfuric acid: In this case we obtained better results at low temperatures compared to higher temperatures: At 30 oC the intermediate ether was 40 % at 90 min and the acetal was 90% at 180 min. The substrate 3-tert-butyl-4-methoxytoluene decreased to 10 %. An amount of 17 % for the 3-tert-butyl-4-methoxybenzaldehyde was observed.6 Direct Electrolysis: Summary and concluding remarks • Benzenesulfonic acid.

for example a 20% yield of the intermediate ether within 60 min and a yield of 60% of acetal was obtained at 40 oC within 90 min. except at low temperature (30 oC) where the yield of acetal was about 90%.103 • Sodium perchlorate: The formation of the desired acetal seemed to be consistent in this case around the 80% mark. . • Potassium fluoride: In the presence of this electrolyte reactions were significantly faster.

The routes that were evaluated through bench scale synthesis studies were: • • • The catalytic air oxidation of the methoxytoluene.104 Chapter 4 SUMMARY AND CONCLUDING REMARKS The following sections were described for the evaluation of the various potential routes to convert alkyl-substituted methoxytoluenes selectively into the corresponding alkyl-substituted methoxybenzaldehydes. and The indirect electrochemical oxidation of the methoxytoluene. and are currently the main route of hydroxybenzaldehyde production.1 Catalytic Air Oxidation The production of alkoxybenzaldehydes is currently based on two starting materials. . In the case of the catalytic air oxidation of methoxytoluenes. namely cresol or phenol. The purpose of these investigations was to be able to identify the most efficient and selective route to produce the desired benzaldehydes in high yield. The direct electrochemical oxidation of the methoxytoluene. Inherent to these reactions are the need for regioselective control. and most commercial processes are optimized in terms of the 2hydroxybenzaldehyde isomer. The phenol-based routes have enjoyed most commercial success. the phenolic group is protected by the ether group and traditional oxidation methods and catalysts may be considered for these oxidations. 4. including the well known cobalt(II) acetate/bromide or cobalt(II) acetate/manganese(II) bromide catalyst system.

as well as the rate (and degree) of substitution during alkylation reactions. It was therefore necessary to establish not only whether the oxidation step should come before or after the alkylation step.2 Catalytic air oxidation: Reaction temperature Being a free-radical reaction. . The reasoning behind this approach was as follows. and to evaluate the feasibility of obtaining high benzaldehyde selectivity at restricted substrate conversions.105 4. Thus. 4.1. in terms of the present system. several oxidation reactions were performed at different reaction temperatures. Of these. but also the selectivity to the desired aldehyde that could be expected from these oxidation reactions. Results obtained clearly suggested that increased electron density on the aromatic ring improves the selectivity to the desired benzaldehyde.1. the selectivity achievable during the catalytic air oxidation step would be the limiting factor due to the ease of further oxidation of the desired aldehyde product. one of two routes can be followed. or initial oxidation to form the benzaldehyde (or a protected form thereof) followed by alkylation.1 Nature of the substrate We have studied the catalytic air oxidation of several alkylbenzenes and substituted alkylbenzenes to determine the effect of substitution on the alkylbenzene ring. In order to investigate the effect of reaction temperature on the oxidation of 4-methoxytoluene and the selectivity to 4-methoxybenzaldehyde. catalytic air oxidation reactions can be expected to be influenced significantly by the reaction temperature at which oxidations are performed. To produce alkyl-substituted methoxybenzaldehydes in high yield by means of catalytic air oxidation. namely initial alkylation of the aromatic ring followed by oxidation. The nature and extent of substitution on the ring will affect both the rate (and extent) of oxidation. one may conclude that it would be desirable to first form the 3-tert-butyl-4-methoxytoluene before carrying out the air oxidation step.

It has.3 Catalytic air oxidation: Effect of catalyst concentration As discussed earlier. This effect is especially noticeable at lower conversion levels. It has also been shown that aldehyde oxidation starts to dominate once the bulk of “inorganic” bromide has been converted into “organic” bromide.02 M.1. however. The observed increase in selectivity is.01 M – 0.106 The results obtained showed that as the temperature increases. been shown that bromide is converted into an inactive form.1. it was important to investigate the effect of increasing water levels in the oxidation mixtures. the selectivity to aldehyde decreases. however. especially as the substrate conversion increases.1 M during the Co-Br-catalysed air oxidation of 4-methoxytoluene. . probably not significant enough to warrant the large increase in catalyst concentration. in particular benzylic bromides. This process destroys the initially active Co(II)-Br catalyst species and which is not readily converted back into an active form. The results obtained clearly showed an increase in 4-methoxybenzaldehyde selectivity as the catalyst concentration is increased from 0.4 Catalytic air oxidation: Effect of water concentration Water is continuously formed during the catalytic air oxidation of organic compounds and since the cobalt-bromide catalyst used during these oxidation reactions are susceptible to hydrolysis. and therefore aldehyde selectivity will decrease as a result of the conversion of the active catalyst species into a non-bromide containing form. 4. the active catalyst during the cobalt(II) acetate bromide catalyzed air oxidations of alkylbenzenes are thought to be a complex containing a direct Co(II) – bromide bond. 4. but at higher conversion levels there is virtually no effect on the selectivity to 4-methoxybenzaldehyde once the cobalt concentration is raised above 0.

the reaction selectivity decreases significantly.2. Such factors are temperature. 85% yield and 95% selectivity for the 3-tert-butyl-4methoxbenzaldehyde was obtained.5%. stirring rate has to be fast enough to give good mass transfer between the mediator and the substrate.5 Catalytic Air Oxidations: Concluding Remarks High aldehyde selectivities of above 70 % could be achieved with the catalytic air oxidation on various substituted alkyl aromatics if the substrate contains electron donating groups on the aromatic ring.2 Indirect Electrochemical Oxidations 4. water content and other reaction variables could be carefully controlled. or when the substrate conversion is restricted to < 30 %.107 The results obtained show an interesting trend in that the selectivity to 4methoxybenzaldehyde improves as the water concentration is increased from 0. rate of stirring and time. Thereafter.2% to about 2. With these conditions an 85% conversion of the 3-tert-butyl-4-methoxtoluene. provided certain factors such as temperature. .1 Ceric Ammonium Reactions It has been found that with the ceric ammonium nitrate oxidation reactions there are major factors that play a role on the rate of the product formation.1. 4. Recycling of the cerium and re-using it to oxidized the substrate have shown no decrease in performance. Temperature was kept constant at 30 oC. 4.

Oxidations carried out using the inorganic mediators ceric ammonium nitrate and cerium (IV) methane sulfonate has shown that these methods are capable of producing significantly improved results compared to catalytic air oxidations. 2M. 4.3 Direct Electrochemistry In this method we used different supporting electrolytes i. reasonable results were achieved. benzene methane sulfonic acid sodium salt. In particular. probably due to over oxidation. 6M. Thus. sodium salt: At low temperatures the reaction is slow but results in a high yield of the desired acetal at 40 oC and 180 min. acetonitrile performs best at 50 oC.108 4. cerium (IV) methane sulfonate is capable of giving the desired product in near quantitative selectivity at substrate conversions as high as 90%.2 Methanesulfonic reactions and the effect of a co-solvent Different concentrations of methanesulfonic acid were investigated i. results in slow mass transfer in these oxidations. . namely. At 8M concentration. 4M. When different organic solvents were used to improve mass transfer between the two reacting phases. dichloromethane at reflux. the selectivity was low. solubility of the substrate. • Benzenesulfonic acid. sodium perchlorate. The low solubility of the substrate in the aqueous methane sulfonic acid solutions. and in the case of acetonitrile. which is probably due to the low concentrations of Ce (IV) after electrolysis.e. temperature and rate of stirring. The use of polar solvents as co-solvents alleviates this problem only slightly. The first two methanesulfonic acid concentrations did not have much effect on the substrate conversion. which led to performing these oxidations at 6M concentration of methanesulfonic acid. 8M. Again there are several factors that played a role in these reactions. potassium flouride and sulfuric acid at different temperatures and different flow rates. and acetone at 21 oC. results in the further oxidation of the desired aldehyde through to the benzoic acid. The two electrodes used were graphite as the anode material and stainless steel as the cathode material. however.e.2.

except at low temperature (30 oC) where the yield of acetal was about 90%. • Potassium fluoride: In the presence of this electrolyte reactions were significantly faster. the reaction is faster and the intermediate ether reaches a maximum of 80%. for example a 20% yield of the intermediate ether within 60 min and a yield of 60% of acetal was obtained at 40 oC within 90 min. • Sodium perchlorate: The formation of the desired acetal seemed to be consistent in this case around the 80% mark. • Sulfuric acid: In this case we obtained better results at low temperatures compared to higher temperatures: At 30 oC the intermediate ether was ca 15 % at 90 min and the acetal was 80% at 180 min. At higher temperatures the acetal concentration reaches a maximum of only about 70%. . In conclusion. for the production of high value fine chemicals over catalytic air oxidation routes. this work has clearly illustrated the potential advantages of electrochemical oxidations. either direct or indirect.109 At high temperature.

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